NCC-PDI Pitch Winners

NCC-PDI announces medical device pitch winners

NCC-PDI Pitch Winners

Five pediatric medical device innovators each captured $50K in funding and access to a new pediatric device accelerator program in a competition hosted April 30, 2019 by National Capital Consortium for Pediatric Device Innovation that focused on orthopedic and spine devices. Clockwise from front left: Kolaleh Eskandanian, Children’s National Health System; Cristian Atria, nView Medical; John Barrett, Auctus Surgical Inc.; Paul Mraz, ApiFix; Dan Sands, AMB Surgical II; Anuradha Dayal, BabySteps, Children’s National Health System; Paul Grand, MedTech Innovator; (center) Bill Bentley, Robert E. Fischell Institute for Biomedical Devices, University of Maryland.

The National Capital Consortium for Pediatric Device Innovation (NCC-PDI) announced five winners of its “Make Your Medical Device Pitch for Kids!” competition held on April 30 at the University of Maryland. Each winner receives $50,000 in grant funding and gains access to the consortium’s first-of-its-kind “Pediatric Device Innovator Accelerator Program” led by MedTech Innovator.

NCC-PDI, one of five FDA Pediatric Device Consortia grant programs that support the development and commercialization of pediatric medical devices, is led by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System and the A. James Clark School of Engineering at the University of Maryland. The consortium recently added new accelerators BioHealth Innovation and MedTech Innovator and design firm partner, Smithwise.

A panel of 32 expert judges from business, healthcare, regulatory and legal sectors selected the winners based on the clinical significance and commercial feasibility of their medical devices for children. The competition focused solely on advancing care in the pediatric orthopedics and spine sector which the FDA identified as an emerging underserved specialty lacking innovation.

The competition winners are:

  • AMB Surgical, LLC, Dayton, Ohio – FLYTE, a device designed to reduce invasive and repetitive surgery in children and teens with orthopedic illnesses such as scoliosis and limb abnormalities
  • Auctus Surgical, Inc., San Francisco, Calif. – Auctus Surgical Dynamic Spinal Tethering System, a mechanism used to correct the scoliotic spine in pediatric patients through a tethering procedure
  • ApiFix Ltd, Boston, Mass. – ApiFix’s Minimally Invasive Deformity Correction (MID-C) System, a posterior dynamic deformity correction system for surgical treatment to provide permanent spinal curve correction while retaining flexibility
  • Children’s National Health System, Washington, D.C.– Babysteps platform to improve initial assessment of clubfoot deformity and predict the magnitude of correction
  • nView Medical, Salt Lake City, Utah – Surgical scanner using AI-based image creation to provide instant 3D imaging during surgery to improve imagery speed and accuracy

“All finalists are winners and we believe that, with NCC-PDI’s support, some of the awarded devices will be available to orthopedic and spine clinicians in the near future. That is vitally important since innovation has been stagnant in this area,” says Kolaleh Eskandanian, Ph.D., MBA, PMP, vice president and chief innovation officer at Children’s National and principal investigator of NCC-PDI. “This competition aims to increase the profile of companies by exposing them to a panel of industry leaders who may become future investors or strategic partners.”

Through the inaugural NCC-PDI “Pediatric Device Innovator Accelerator Program,” MedTech Innovator is providing winners with virtual in-depth, customized mentorship from some of the industry’s leading executives and investors. MedTech Innovator has a proven track record of identifying early-stage medical device companies with the key characteristics required for commercial success and accelerating their growth through its vast ecosystem of resources.

“As a pediatric orthopedic surgeon, I am encouraged by the innovations presented at this competition,” says Matthew Oetgen, M.D., division chief of Orthopaedic Surgery and Sports Medicine at Children’s National, who served on the judging panel. “We need more devices that compensate for the smaller size of children compared to adults and that can adapt as children’s bones continue to grow and develop. The finalists who competed fully embraced that challenge.”

This was NCC-PDI’s eighth competition in six years and a ninth competition is planned for fall 2019 that focuses on NICU. Including this recent round of winners, the consortium has supported 94 pediatric medical devices and helped five companies receive FDA or CE mark regulatory clearance.

To learn more about the winners and the fall 2019 pitch competition, visit the National Capital Consortium for Pediatric Device Innovation website.

M and her daughter

Tracing the history of aggrecan gene mutations

M and her daughter

M takes a photo with her daughter in Washington, where they learned they have an ACAN gene mutation that causes short stature.

On Sunday, April 28, 2019 a team of researchers received the 2019 Human Growth Award at the Pediatric Endocrine Society’s Annual Meeting for their abstract, entitled “Clinical Characterization and Trial of Growth Hormone in Patients with Aggrecan Deficiency: 6 Month Data,” and presented this at the PES Presidential Poster Session.

Eirene Alexadrou, M.D., a fellow at Cincinnati Children’s Hospital Medical Center, accepted the award and honorarium, while ongoing research is underway. This study started in 2017, with the objective of characterizing the phenotypic spectrum and response to a standardized regimen of growth hormone in a small cohort of 10 patients and their families.

In 2017, Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System, led an international consortium of researchers in publishing a manuscript describing the phenotypic spectrum of 103 individuals – 70 adults and 33 children, including 57 females and 46 males – from 20 families with aggrecan gene (ACAN) mutations.

Dr. Dauber and his colleagues have established that short stature and accelerated bone age is common among people with ACAN mutations. In a review of retrospective data, including patients treated with a variety of growth-promoting therapies at varying doses, the research team found that over the first one, two and three years of treatment, the standard deviation scores (SDS) for height increased by .4, .7 and 1, respectively. The current abstract now describes seven children enrolled in a prospective standardized trial of growth hormone therapy. After six months of treatment, the children have increased their height SDS by an average of 0.46.

Additionally, the researchers are performing an in-depth look at the joint effects, including special MRIs of the knees. They found that two of the children had a problem with their knee cartilage called osteochondritis dissecans. They had not yet presented with clinical symptoms. The researchers hope that early intervention with physical therapy can help prevent significant joint disease in the future.

M and her mother and daughter in Cincinnati

M, her daughter, and M’s mother take a photo in Cincinatti, where they are pariticipating in a clinical trial for aggrecan deficiency.

“Providing growth hormone therapy to children with ACAN gene mutations is relatively new in the field of pediatric endocrinology,” notes Dr. Dauber. “Previously, the assumption was that this was just short stature. We’ll continue to diagnose ACAN mutations in a clinical setting and work with families to reduce the risk of complications, such as joint problems or early-onset arthritis, which may co-occur with this gene mutation.”

As an example, Dr. Dauber met an 8-year-old patient several months ago who presented with symptoms of short stature. The patient is healthy, confident and still growing so her mother wasn’t worried about her but she made the appointment to see if there was an underlying cause to her daughter’s short stature. Her family history revealed clues to an ACAN mutation, which was later confirmed through genetic tests. Her mom, M, stands 4’8; her grandmother is 4’9. Her great grandmother was short and her great, great grandfather was 5’1. Short stature and joint problems run in the family. Once M mentioned she had osteochondritis dissecans and a hip replacement, she provided a textbook case study for carrying the ACAN mutation.

After the appointment, M shared the news with her mother about the possibility of having aggrecan deficiency. After taking genetic tests, M, her mother and M’s daughter learned they all have the ACAN mutation, and enrolled in the study that Dr. Dauber is guiding. Suddenly, it all made sense. After examining family photos, they traced the ACAN mutation back through four generations.

They could tell what relatives had an altered copy of the ACAN gene. M had it, while her two sisters did not. M’s mother was an only child, so she didn’t have aunts or uncles to compare her mother’s height to, but M’s grandmother was short, while her grandmother’s brother was average height. Although her mother’s family was from Germany, she learned that there is no specific ancestry associated with this mutation. It happens by chance and is passed down from a single parent to, on average, half of their children, a form of genetic inheritance called autosomal dominant transmission.

Ms great grandmother and grandfather

M’s great grandfather was noticeably shorter than her great grandmother, who was 5’4.

Through further research, M learned that the ACAN gene provides instructions for producing aggrecan protein, which is essential for bone growth, as well as for the stability of cartilage that lines bones and joints, explaining her recurring joint problems.

She also looked into the future, examining potential risk factors for her daughter: joint pain and bone conditions, which could contribute to arthritis, hip dysplasia and back problems.

The diagnosis now makes it easier for M and her daughter to favor bone-building activities that are easy on the joints, like swimming or water aerobics, instead of gymnastics and weight lifting. After having a hip replacement, M was careful to supplement with calcium and vitamin D. Now, she’ll take the same steps to ensure optimal bone health for her daughter. She’ll work with orthopedic specialists as her daughter grows into her pre-teen and adolescent years, carefully monitoring joint pain – altering activities that are tough on the joints, as necessary.

M let her daughter make a decision about growth hormone therapy, which she decided to try. The benefits of the treatment, increased height, carry inconveniences, such as taking daily shots, but they are sticking with it.

“We’re at the tip of the iceberg with research that explores this gene mutation,” says Dr. Dauber. “We’ll continue to study these families, and more, over time to assess growth patterns and  gene expression, which may reveal other mutations associated with short stature or joint problems, and guide future treatment options. It was a coincidence that this family had the ACAN mutation and scheduled an appointment, while we’re conducting this study. Otherwise, they may not have had an answer since this is fairly new research.”

M and her daughter are happy to be part of this study, which they will participate in for the next few years. M’s mother is also glad to participate. She made a different choice, decades ago, to reject hormone treatment when it was offered to her for undiagnosed short stature, but she’s sharing genetic clues, which may influence treatment options for her granddaughter and for her family’s next generation.

The original study, “Clinical Characterization of Patients with Autosomal Dominant Short Stature due to Aggrecan Muations,” appeared in the Feb. 2017 issue of the Journal of Clinical Endocrinology and Metabolism, and published as an online advance on Nov. 21, 2016.

Thirty-six researchers collaborated on this original paper, which was funded by 16 international health institutes and foundations, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, the Swedish Research Council, the Swedish Governmental Agency for Innovation Systems, the Marianne and Marcus Wallenberg Foundation, the Stockholm County Council, the Swedish Society of Medicine, Byggmastare Olle Engkvist’s Foundation, the Sao Paulo Research Foundation, the Spanish Ministry of Education and Science, the Czech Health Research Council and the Ministry of Health, Czech Republic.

DNA Molecule

Using genomics to solve a 20-year case study

DNA Molecule

“The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought all together,” says Andrew Dauber, M.D., MMSc.

After 20 years, a patient’s family received an answer to a decades-long genetic mystery. Their daughter had two rare disorders, Angelman syndrome and P450scc deficiency, which was detected after researchers found out she had uniparental disomy, two copies of chromosome 15 from one parent and none from another.

The research paper, entitled “Adrenal Insufficiency, Sex Reversal and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1,” was published on March 22, 2018, and recognized as the best novel insight paper published by Hormone Research in Paediatrics in 2018, announced at the Pediatric Endocrine Society’s Annual Meeting in Baltimore on Saturday, April 27, 2019.

By using a variety of genetic tools, including whole-exome sequencing, microarray analyses and in-vitro modeling for gene splicing, the researchers were able to confirm this patient had uniparental disomy, a recessive genetic condition. They learned that after she received two impaired copies of chromosome 15 from her father, this woman developed a hormonal problem that led to adrenal insufficiency and sex reversal. This explained why she physically presented as a female, despite having testes and a Y-chromosome. It also explained other symptoms, including developmental delays and seizures.

“It’s a unique conglomeration of symptoms, manifested by the combination of these two very rare disorders,” says Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System and a guiding research author of this study. “The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought together, commencing a 20-year diagnostic odyssey.”

For example, each of the conditions this patient has is known and rare: Angelman syndrome affects about one in 10 to 20,000 people in the U.S. Typical symptoms include those observed in this patient: delayed development, intellectual disability, speech impairment and seizures. Side-chain cleavage disorder, which leads to adrenal disorders and sex reversal, is also very rare. In 2005 the chances of survival with a P450scc defect were slim, but since then more than 28 infants have been diagnosed with this gene deficiency, which is required to convert cholesterol to pregnenolone, a hormone in the adrenal gland.

Dr. Dauber notes the chances of this occurring again are highly unlikely. The odds here are one in a gazillion. In this case, one disorder unmasked another, leaving researchers with new insights into the methodology for unraveling ultra-rare genetic disorders or for more common rare conditions.

“Knowing about the gene that caused the adrenal insufficiency and understanding this etiology won’t change medical care for this patient, but it will change the way researchers think about genetic detective work and about combining different technologies,” says Dr. Dauber. “We know that genetic disorders can be complex presentations of different disorders combined. This patient didn’t have one disorder, but three.”

When asked about the significance of the award, Dr. Dauber notes that, “It’s not that other people haven’t recognized this concept before, but this case is a striking example of it. Different technologies will unveil different types of genetic changes, which is why you have to use the right technology or the right technologies in the right combination to piece together the whole picture.”

Ahlee Kim, M.D., the lead study author and a clinical research fellow at Cincinnati Children’s Hospital Medical Center, will receive the award and the honorarium.

Additional study authors include Masanobu Fujimoto, Ph.D., Vivian Hwa, Ph.D., and Philippe Backeljauw, M.D., from Cincinnati Children’s Hospital.

The research was supported by grant K23HD07335, awarded to Dr. Dauber, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Additional funding included grant 1UL1TR001425 from the NIH’s National Center for Advancing Translational Sciences.

DNA Molecule

Decoding cellular signals linked to hypospadias

DNA Molecule

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” Daniel Casella, M.D. says.

Daniel Casella, M.D., a urologist at Children’s National, was honored with an AUA Mid-Atlantic Section William D. Steers, M.D. Award, which provides two years of dedicated research funding that he will use to better understand the genetic causes for hypospadias.

With over 7,000 new cases a year in the U.S., hypospadias is a common birth defect that occurs when the urethra, the tube that transports urine out of the body, does not form completely in males.

Dr. Casella has identified a unique subset of cells in the developing urethra that have stopped dividing but remain metabolically active and are thought to represent a novel signaling center. He likens them to doing the work of a construction foreman. “If you’re constructing a building, you need to make sure that everyone follows the blueprints.  We believe that these developmentally senescent cells are sending important signals that define how the urethra is formed,” he says.

His project also will help to standardize the characterization of hypospadias. Hypospadias is classically associated with a downward bend to the penis, a urethra that does not extend to the head of the penis and incomplete formation of the foreskin. Still, there is significant variability among patients’ anatomy and to date, no standardized method for documenting hypospadias anatomy.

“Some surgeons take measurements in the operating room, but without a standardized classification system, there is no definitive way to compare measurements among providers or standardize diagnoses from measurements that every surgeon makes,” he adds. “What one surgeon may call ‘distal’ may be called ‘midshaft’ by another.” (With distal hypospadias, the urethra opening is near the penis head; with midshaft hypospadias, the urethra opening occurs along the penis shaft.)

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” he says.

Parents worry about lingering social stigma, since some boys with hypospadias are unable to urinate while standing, and in older children the condition can be associated with difficulties having sex. Surgical correction of hypospadias traditionally is performed when children are between 6 months to 1 year old.

When reviewing treatment options with family, “discussing the surgery and postoperative care is straight forward. The hard part of our discussion is not having good answers to questions about long-term outcomes,” he says.

Dr. Casella’s study hopes to build the framework to enable that basic research to be done.

“Say we wanted to do a study to see how patients are doing 15-20 years after their surgery.  If we go to their charts now, often we can’t accurately describe their anatomy prior to surgery.  By establishing uniform measurement baselines, we can accurately track long-term outcomes since we’ll know what condition that child started with and where they ended up,” he says.

Dr. Casella’s research project will be conducted at Children’s National under the mentorship of Eric Vilain, M.D., Ph.D., an international expert in sex and genitalia development; Dolores J. Lamb, Ph.D., HCLD, an established leader in urology based at Weill Cornell Medicine; and Marius George Linguraru, DPhil, MA, MSc, an expert in image processing and artificial intelligence.

Mark Batshaw

40 years, 8 editions: Writing “Children With Disabilities”

Mark Batshaw

Forty years ago, Mark L. Batshaw, M.D., almost singlehandedly wrote a 23-chapter first edition that ran about 300 pages. Now Dr. Batshaw’s tome, “Children With Disabilities,” is in its eighth edition, and this new volume is almost 1,000 pages, with 42 chapters, two co-editors and over 35 authors from Children’s National.

Back in 1978, Mark L. Batshaw, M.D., was a junior faculty member at John’s Hopkins University School of Medicine. In the evenings he taught a course in the university’s School of Education  titled “The Medical and Physical Aspects of the Handicapped Child,” for Master’s level special education students. Because no textbook at that time focused on that specific topic, Batshaw developed his own slide set.

“At the end of the first year of teaching the course my students said ‘You really ought to consider writing a text book based on your slides to help us move forward,’ ” Dr. Batshaw recalls. The father of three carved out time by writing on weekends and at night, cutting back on sleep.

His first goal was to create a textbook that would serve as a curriculum for a series of courses that would be taught at universities to specialists who work with children with disabilities, including social workers, physical and occupational therapists, speech and language pathologists, special education teachers, nurses, doctors and dentists.

“I wanted to cover the whole range of disabilities and divided the book initially into a series of sections, including embryology, to help students understand what can go wrong in fetal development to lead to a developmental disability; and chapters on each developmental disability, including autism, attention-deficit/hyperactivity disorder (ADHD), cerebral palsy, learning disabilities and traumatic brain injury,” he says. “The third section was devoted to available treatments, including occupational and physical therapy, speech language therapy, nutrition and medications. The final section focused on outcomes.”

His second aim was for the book to serve as a reference text for professionals in the field. The 33-year-old contacted a brand-new new publisher, Paul H. Brookes Publishing Co., that focused on special education. “They took a chance on me, and I took a chance on them,” he says.

Forty years ago, he almost singlehandedly produced a 23-chapter first edition that ran about 300 pages. Now Dr. Batshaw’s tome is in its eighth edition, and this new volume is almost 1,000 pages. And, rather than being its sole author, Dr. Batshaw enlisted two co-editors and at least five dozen authors who contributed specialty expertise in genetic counseling, social work, physical and occupational therapy, medicine and nursing. His daughter, Elissa, a special education teacher and school psychologist, authored a chapter about special education services, and his son, Drew, an executive at a start-up company, contributed autobiographical letters about the effect ADHD has had on his life.

The book, “Children With Disabilities,” also includes:

  • A glossary of medical terms so that as the reader reviews patient reports they can easily look up an unfamiliar term
  • An appendix on commonly used drugs to treat children with disabilities in order to look up the medicine by name and see the range of doses
  • An appendix devoted to different syndromes children might have
  • A reference section with organizations and foundations that help children with disabilities
  • A web site with sections designed for students and other content designed for teachers with thought questions to guide practical use of information in each chapter and more than 450 customizable PowerPoint slides for download
  • Call-out boxes for interdisciplinary team members, such as genetic counselors, explaining the roles they serve and their educational background, and
  • Excerpts of recent research articles.

“The students say they don’t sell the book. Usually when students have a textbook, they try to sell it second hand after the course ends,” explains Dr. Batshaw, now Executive Vice President, Physician-in-Chief and Chief Academic Officer at Children’s National. “Instead, students keep it and use it as a practical reference as they become professionals in their field. It has had the impact I had hoped for both as a textbook and a reference book: They say they refer to it when they have patients with a particular disorder they’re not used to treating to read up on it.”

Now a bestseller, there are more than 200,000 copies in print, including Portuguese and Ukrainian translations. “It didn’t start that way. It grew organically,” he says.

In addition to Dr. Batshaw, Children’s contributors to “Children With Disabilities” include Nicholas Ah Mew, M.D., pediatric geneticist; Nickie N. Andescavage, M.D., neonatologist; Mackenzie E. Brown, D.O., fellow in Pediatric Rehabilitation Medicine; Justin M. Burton, M.D., chief, Division of Pediatric Rehabilitation Medicine; Gabrielle Sky Cardwell, BA, clinical research assistant; Catherine Larsen Coley, PT, DPT, PCS, physical therapist; Laurie S. Conklin, M.D., pediatric gastroenterologist; Denice Cora-Bramble, M.D., MBA, executive vice president and chief medical officer; Heather de Beaufort, M.D., pediatric ophthalmologist; Dewi Frances T. Depositario-Cabacar, M.D., pediatric neurologist; Lina Diaz-Calderon, M.D., fellow in Pediatric Gastroenterology; Olanrewaju O. Falusi, M.D., associate medical director of municipal and regional affairs, Child Health Advocacy Institute; Melissa Fleming, M.D., pediatric rehabilitation specialist; William Davis Gaillard, M.D., chief Division of Epilepsy, Neurophysiology and Critical Care; Satvika Garg, Ph.D., occupational therapist; Virginia C. Gebus, R.N., MSN, APN, CNSC, nutritionist; Monika K. Goyal, M.D., MSCE, assistant chief, Division of Emergency Medicine; Andrea Gropman, M.D., chief, Division of Neurodevelopmental Pediatrics and Neurogenetics, geneticist and Neurodevelopmental pediatrician; Mary A. Hadley, BS, senior executive assistant; Susan Keller, MLS., MS-HIT, research librarian; Lauren Kenworthy, Ph.D., director, Center for Autism Spectrum Disorders; Monisha S. Kisling, MS, CGC, genetic counselor; Eyby Leon, M.D., pediatric geneticist; Erin MacLeod, Ph.D., RD, LD, director, Metabolic Nutrition; Margaret B. Menzel, MS, CGC, genetic counselor; Shogo John Miyagi, Ph.D., PharmD, BCPPS, Pediatric Clinical Pharmacology fellow; Mitali Y. Patel, DDS, program director, Pediatric Dentistry; Deborah Potvin, Ph.D., neuropsychologist; Cara E. Pugliese, Ph.D., clinical psychologist; Khodayar Rais-Bahrami, M.D., neonatologist and director, Neonatal-Perinatal Medicine Fellowship Program; Allison B. Ratto, Ph.D., clinical psychologist; Adelaide S. Robb, M.D., chief, Division of Psychiatry and Behavioral Sciences; Joseph Scafidi, D.O., neonatal neurologist; Erik Scheifele, D.M.D., chief, Division of Oral Health; Rhonda L. Schonberg, MS, CGC, genetic counselor; Billie Lou Short, M.D., chief, Division of Neonatology; Kara L. Simpson, MS, CGC, genetic counselor; Anupama Rao Tate, D.M.D., MPH, pediatric dentist; Lisa Tuchman, M.D., chief, Division of Adolescent and Young Adult Medicine; Johannes N. van den Anker, M.D., Ph.D., FCP, chief, Division of Clinical Pharmacology, Vice Chair of Experimental Therapeutics; Miriam Weiss, CPNP-PC, nurse practitioner; and Tesfaye Getaneh Zelleke, M.D., pediatric neurologist.

Billie Lou Short and Kurt Newman at Research and Education Week

Research and Education Week honors innovative science

Billie Lou Short and Kurt Newman at Research and Education Week

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents:
Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students:
Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty:
Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students:
Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents:
Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students:
Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty:
Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff:
Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents:
Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students:
Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty:
Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff:
Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents:
Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students:
Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Beth Tarini

Getting to know SPR’s future President, Beth Tarini, M.D., MS

Beth Tarini

Quick. Name four pillar pediatric organizations on the vanguard of advancing pediatric research.

Most researchers and clinicians can rattle off the names of the Academic Pediatric Association, the American Academy of Pediatrics and the American Pediatric Society. But that fourth one, the Society for Pediatric Research (SPR), is a little trickier. While many know SPR, a lot of research-clinicians simply do not.

Over the next few years, Beth A. Tarini, M.D., MS, will make it her personal mission to ensure that more pediatric researchers get to know SPR and are so excited about the organization that they become active members. In May 2019 Dr. Tarini becomes Vice President of the society that aims to stitch together an international network of interdisciplinary researchers to improve kids’ health. Four-year SPR leadership terms begin with Vice President before transitioning to President-Elect, President and Past-President, each for one year.

Dr. Tarini says she looks forward to working with other SPR leaders to find ways to build more productive, collaborative professional networks among faculty, especially emerging junior faculty. “Facilitating ways to network for research and professional reasons across pediatric research is vital – albeit easier said than done. I have been told I’m a connector, so I hope to leverage that skill in this new role,” says Dr. Tarini, associate director for Children’s Center for Translational Research.

“I’m delighted that Dr. Tarini was elected to this leadership position, and I am impressed by her vision of improving SPR’s outreach efforts,” says Mark Batshaw, M.D., Executive Vice President, Chief Academic Officer and Physician-in-Chief at Children’s National. “Her goal of engaging potential members in networking through a variety of ways – face-to-face as well as leveraging digital platforms like Twitter, Facebook and LinkedIn – and her focus on engaging junior faculty will help strengthen SPR membership in the near term and long term.”

Dr. Tarini adds: “Success to me would be leaving after four years with more faculty – especially junior faculty – approaching membership in SPR with the knowledge and enthusiasm that they bring to membership in other pediatric societies.”

SPR requires that its members not simply conduct research, but move the needle in their chosen discipline. In her research, Dr. Tarini has focused on ensuring that population-based newborn screening programs function efficiently and effectively with fewer hiccups at any place along the process.

Thanks to a heel stick to draw blood, an oxygen measurement, and a hearing test, U.S. babies are screened for select inherited health conditions, expediting treatment for infants and reducing the chances they’ll experience long-term health consequences.

“The complexity of this program that is able to test nearly all 4 million babies in the U.S. each year is nothing short of astounding. You have to know the child is born – anywhere in the state – and then between 24 and 48 hours of birth you have to do testing onsite, obtain a specific type of blood sample, send the blood sample to an off-site lab quickly, test the sample, find the child if the test is out of range, get the child evaluated and tested for the condition, then send them for treatment. Given the time pressures as well as the coordination of numerous people and organizations, the fact that this happens routinely is amazing. And like any complex process, there is always room for improvement,” she says.

Dr. Tarini’s research efforts have focused on those process improvements.

As just one example, the Advisory Committee on Heritable Disorders in Newborns and Children, a federal advisory committee on which she serves, was discussing how to eliminate delays in specimen processing to provide speedier results to families. One possible solution floated was to open labs all seven days, rather than just five days a week. Dr. Tarini advocated for partnering with health care engineers who could help model ways to make the specimen transport process more efficient, just like airlines and mail delivery services. A more efficient and effective solution was to match the specimen pick-up and delivery times more closely with the lab’s operational times – which maximizes lab resources and shortens wait times for parents.

Conceptual modeling comes so easily for her that she often leaps out of her seat mid-sentence, underscoring a point by jotting thoughts on a white board, doing it so often that her pens have run dry.

“It’s like a bus schedule: You want to find a bus that not only takes you to your destination but gets you there on time,” she says.

Dr. Tarini’s current observational study looks for opportunities to improve how parents in Minnesota and Iowa are given out-of-range newborn screening test results – especially false positives – and how that experience might shake their confidence in their child’s health as well as heighten their own stress level.

“After a false positive test result, are there parents who walk away from newborn screening with lingering stress about their child’s health? Can we predict who those parents might be and help them?” she asks.

Among the challenges is the newborn screening occurs so quickly after delivery that some emotionally and physically exhausted parents may not remember it was done. Then they get a call from the state with ominous results. Another challenge is standardizing communication approaches across dozens of birthing centers and hospitals.

“We know parents are concerned after receiving a false positive result, and some worry their infant remains vulnerable,” she says. “Can we change how we communicate – not just what we say, but how we say it – to alleviate those concerns?”

The Rare Disease Institute staff on Rare Disease Day

Genetics 101: Rare diseases aren’t rare

The Rare Disease Institute staff on Rare Disease Day

Children’s National Health System is home to the Rare Disease Institute, the National Organization for Rare Disease’s first Center of Excellence, the largest clinical genetics program in the United States.

With the advent of DNA databanks, informatics, new technology, pediatric consortiums and global partnerships, clinical researchers have never been in a better position to diagnose and treat rare diseases. A rare disease is categorically defined as a condition that affects less than 200,000 people. However, 25 to 30 million Americans, about one in 10, have a rare disease.

Accelerations in genetic research and diagnostic criteria remain one of the most significant accomplishments in medicine, but these breakthroughs invite new challenges: How will researchers provide ongoing care and treatment for patients navigating a rare disease? How can doctors and researchers multiply themselves to ensure everyone has the latest information and resources they need? How can researchers use existing trials to augment other fields? How can we diagnose, catalogue and treat hundreds of new rare diseases each year, while accelerating the research and care of 7,000 existing rare conditions?

If these questions intrigue you, excite you and make you want to collaborate with scientific peers, welcome to the field of genetics. A common theme researchers and families talk about is that rare diseases affect a small proportion of the population, but have a huge impact.

On April 10, 1,200 international researchers, lawmakers, scientists and drug developers from 50 countries will meet in Oxon Hill, Md., 10 miles south of Washington, for a three-day summit, the World Orphan Drug Congress USA, to discuss how to unify efforts to enhance and maximize care for rare disease patients.

Here are eight themes to keep in mind:

  1. Rare diseases are chronic diseases. The human genome project has enabled the molecular mapping of 8,000 diseases with genetic underpinnings. Of these diseases, 600 diseases have therapies. A child born with a urea cycle disorder had a 5% chance of surviving the disease 40 years ago. Now the survival rate is 95%. Helping children survive is essential, but we need to think about the best treatments and standards for long-term care.
  2. Rare diseases are expensive. In Western Australia, according to the 2010 Western Australia Population Cohort, rare diseases account for less than 5% of hospital visits but for 10% of hospital costs. Similar data from Cleveland finds one-third of pediatric hospital visits have a genetic link but account for half of hospital costs.
  3. Rare diseases share common links. We’ve diagnosed 7,000 rare diseases but there are more to unravel. For example, breast cancer has over 30 molecular subtypes – some of which turn into rare diseases. By better understanding these molecular pathways, we may be able to inform common fields of medicine.
  4. Marshall Summar's Rare Disease 101 presentation

    Dr. Marshall Summar, a medical geneticist, speaks about the future of rare disease research and treatment at a Rare Disease 101 lecture hosted by the Rare Disease Congressional Caucus on Capitol Hill on Feb. 27. To sustain discoveries, Dr. Summar mentions a digital-first, flexible mindset is essential. Standard language and scalable, universal reference structures are required.

  5. Global partnerships create research repositories. Gold-standard research models – double blind, controlled studies with numerous participants – aren’t possible if five people in the world share the same disease. To increase the number of study participants, global partnerships and longitudinal registries are essential.
  6. Standard language helps. To avoid replicating existing research and to help teams quickly reference findings, we need to adopt standardized language to quantify measurements. Researchers from Berlin and Brazil may help inform the etiology of and future treatments for PKU, but they need to manage, store, access and share their collective findings, while remaining flexible.
  7. The science is here. The FDA is approving more drugs for rare diseases than ever before including gene therapy and micro organs, or Rare Diseases-on-chip models. The challenge with treating so many rare diseases isn’t developing new research, but creating therapies and studies to accommodate this patient volume. About 250 rare disease discoveries happen each year. At the current rate, it will take 2,000 years to treat them all.
  8. Progress is here. The Orphan Drug Act fast-tracked approval for rare disease treatments and therapies, and nearly half of all drugs coming in for FDA approval are for rare diseases. However, only 5% of rare diseases have FDA-approved drugs.
  9. We need to replicate geneticists. To provide optimal care, doctors need to standardize education models and use new forms of technology, such as artificial intelligence and deep learning, to share resources faster via patient education portals, resources for families, CME courses and virtual connections with pediatricians or families.

If you would like to learn more or get involved, watch this international summit, the Rare Disease Day Policy Event, which took place at the United Nations Headquarters in New York on Feb. 21. (Some of these issues are covered in video 4.)

If you are a patient, download this patient toolkit from the National Center for Advanced Translational Sciences.

If you live in Washington, D.C., follow the genetics team and consider working with us as we move into a new home, the Children’s National Research and Innovation Campus, in 2020.

Zhe Han

$2M NIH grant for treating disease linked to APOL1

Zhe Han

Children’s researcher Zhe Han, Ph.D., has received a $2 million award from the National Institutes of Health (NIH) to study new approaches to treat kidney disease linked to inheriting Apolipoprotein L1 (APOL1) risk alleles. These risk alleles are particularly common among persons of recent African descent, and African Americans are disproportionately affected by the increased risk in kidney disease associated with these risk alleles.

Han, an associate professor in Children’s Center for Genetic Medicine Research, has established a leading research program that uses the fruit fly Drosophila as a model system to study how genetic mutations lead to disease.

Drosophila is a very basic model, but studies in the fly have led to major breakthroughs in understanding fundamental biological processes that underlie health and disease in humans,” Han says. “Since coming to Children’s National five years ago, I have focused a significant part of my research studying particular fly cells called nephrocytes that carry out many of the important roles of human kidney glomeruli, units within the kidney where blood is cleaned. Working together with clinician colleagues here, we have demonstrated that these Drosophila cells can be used to very efficiently study different types of renal disease caused by genetic mutations.”

The APOL1 risk alleles are genetic variants, termed G1 and G2, found almost exclusively in people of African ancestry and can lead to a four-fold higher risk of end-stage kidney disease, the last of five stages of chronic kidney disease. Exactly how inheriting these risk alleles increases the risk of kidney disease remains an unanswered question and the focus of considerable research activity. Han’s laboratory has developed a Drosophila model of APOL1-linked renal disease by producing the G1 and G2 forms of APOL1 specifically in nephrocytes. This led to defects in fly renal cells that strikingly overlap with disease-associated changes in experimental model and human kidney cells expressing APOL1 risk alleles.

The new NIH award will fund large-scale screening and functional testing to identify new treatment targets and new drugs to treat kidney disease linked to APOL1. Using a genetic screening approach, Han’s lab will identify nephrocyte “modifier” genes that interact with APOL1 proteins and counter the toxic effects of risk-associated G1 and G2 variants.

The team also will identify nephrocyte genes that are turned on or off in the presence of APOL1 risk alleles, and confirm that such “downstream” APOL1-regulated genes are similarly affected in experimental model and human kidney cells. The potential of the newly identified “modifier” and “downstream” genes to serve as targets of novel therapeutic interventions will be experimentally tested in fly nephrocytes in vivo and in cultured mammalian kidney cells.

Finally, the Drosophila model will be used as a drug screening platform for in vivo evaluation of positive “hits” from a cell-based APOL1 drug screening study in order to identify compounds that are most effective with the fewest side effects.

“These types of studies can be most efficiently performed in Drosophila,” Han adds.  “They take advantage of the speed and low cost of the fly model system and the amazing array of well-established, sophisticated genetic tools available for the fly. Using this model to elucidate human disease mechanisms and to identify new effective therapies has truly become my research passion.”

Test tube that says IGF-1 test

A new algorithm: Using genomics and EHR to detect severe growth disorders

Test tube that says IGF-1 test

Andrew Dauber, M.D., MMSc., a pediatric endocrinologist and the chief of endocrinology at Children’s National, guided research presented at ENDO 2019, the Endocrine Society’s annual meeting, enabling clinicians and researchers to understand the genetic underpinnings of certain pediatric growth disorders, while using electronic health record (EHR) algorithms to screen for presenting symptoms in the exam room. In some cases, this prompts further genetic testing and shortens the diagnostic odyssey for pediatric growth disorders – such as Turner syndrome.

Here is a summary of the research findings, delivered as two oral abstracts and a poster session.

ABSTRACT 1: Presented on Saturday, March 23, at 12:30 p.m. CST

Healthy childhood growth cohort provides insight into PAPPA2 and IGF-1 relationship, revealing a new level of complexity to the biology of growth with implications for the study and treatment of severe growth disorders

Program: Growth, puberty, and insulin action and resistance

Session OR07-5: A Cross-Sectional Study of IGF-I Bioavailability through Childhood: Associations with PAPP-A2 and Anthropometric Data

Background: Insulin-like growth factor 1 (IGF-1) is a hormone essential for human growth and is often bound to IGFBP-3, an IGF binding protein. Pregnancy Associated Plasma Protein-A2 (PAPP-A2) cleaves intact IGFBP-3, freeing IGF-1 to support normal growth functions. This is the first study, led by Dr. Andrew Dauber with collaborators from Cincinnati Children’s Hospital Medical Center, to track PAPP-A2 and intact IGFBP-3 concentrations throughout childhood. The research team studied 838 healthy children, ages 3-18, in the Cincinnati Genomic Control Cohort, to better understand patterns of growth and development by examining the relationship between PAPPA2 and IGF-1 bioavailability.

Study results: Free IGF-1 increased with age. PAPP-A2, a positive modulator of IGF-1 bioavailablity, decreased with age, which surprised the researchers, and is not positively associated with absolute levels of free IGF-1. However, higher levels of PAPP-A2 cleave IGFBP-3 resulting in lower levels of intact IGFBP-3, and consequently, increasing the percentage of free to total IGF-1. This demonstrates that PAPP-A2 is a key regulator of IGF-1 bioavailability on a population-wide scale.

Impact: This research may help endocrinologists create unique, targeted treatment for children with PAPPA2 mutations and could help stratify patients with potential risk factors, such as IGF-1 resistance due to increased binding of IGF-1, associated with severe growth and height disorders. See adjoining study below.

Watch: Video interview with Dr. Dauber

ABSTRACT 2: Presented on Saturday, March 23, at 12:45 p.m. CST

Electronic health records can alert physicians to patients who could benefit from genetic testing to identify severe growth disorders

Program: Growth, puberty, and insulin action and resistance

Session OR07-6: Integrating Targeted Bioinformatic Searches of the Electronic Health Records and Genomic Testing Identifies a Molecular Diagnosis in Three Patients with Undiagnosed Short Stature

Background: Despite referrals to pediatric endocrinologists and extensive hormonal analysis, children with short stature due to a genetic cause, may not receive a diagnosis. Electronic health records may help identify patients – based on associated phenotypes and clinical parameters – who could benefit from genetic testing.

Study results: Researchers from three children’s hospitals – Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital Medical Center – gathered data, starting small, with a known variable, or phenotype, associated with severe growth disorders: insulin-like growth factor 1 (IGF-1) resistance. A targeted bioinformatics search of electronic health records led the team to identify 39 eligible patients out of 234 candidates who met the criteria for a possible genetic-linked growth disorder. Participants were included if their height fell below two standard deviations for age and sex and if their IGF-1 levels rose above the 90th percentile. Patients who had a chronic illness, an underlying genetic condition or precocious puberty were excluded. Whole-exome sequencing (WES) was performed on DNA extracted from willing participants, including 10 patients and their immediate family members. The research team identified new genetic causes in three out of 10 patients with severe growth disorders, who were previously missed as having a genetic-linked growth disorder.

Note: Two patients had two novel IGF1R gene variants; a third had a novel CHD2 variant (p. Val540Phe). The two patients with IGF1R variants had a maternally inherited single amino acid deletion (p.Thr28del) and a novel missense variant (p. Val1013Phe).

Impact: Similar EHR algorithms can be replicated to identify pediatric patients at risk for or thought to have other genetic disorders, while expanding genetic research and improving patient care.

Watch: Video interview with Dr. Dauber

POSTER: Presented on Monday, March 25, at 1 p.m. CST

Electronic health record alerts could help detect Turner syndrome, shorten diagnostic odyssey for girls born with a missing or partially-deleted X chromosome

Program: Session P54. Pediatric puberty, ovarian function, transgender medicine and obesity

Poster Board #MON-249: Algorithm-Driven Electronic Health Record Notification Enhances the Detection of Turner Syndrome

Background: Turner syndrome (TS) results from a complete or partial loss of the second X chromosome and affects about one in every 2,500 female births. TS is common in females with unexplained short stature, but the diagnosis is often not made until late childhood (8-9 years), leading to delays in treatment and screening for comorbidities, such as heart conditions, chronic ear infections, vision problems and challenges with non-verbal learning. Using electronic health record (EHR) alarms can help clinicians screen for and diagnose TS patients earlier in life.

Study results: Researchers from Cincinnati Children’s Hospital Medical Center searched EHRs for female patients with idiopathic short stature who met the team’s selection criteria: Their height fell below two standard deviations from the mean for age as well as one standard deviation below the mid-parental height, had a BMI greater than 5 percent and did not have a chronic illness. The search produced 189 patients who met the diagnostic criteria, 72 of whom had not received prior genetic testing. Out of genetic samples available, 37 were compatible for a microarray analysis – which helped the team identify two cases of TS and a third chromosomal abnormality, all of which were missed by routine clinical evaluation.

Impact: DNA samples may not be available for all patients, but clinicians and researchers can identify and integrate tools into EHR’s – creating their own algorithms. An example includes setting up alerts for specific growth parameters, which helps identify and screen patients for TS.

The abstracts Dr. Dauber and his team discuss at ENDO 2019 support ongoing research, including a partnership among four leading children’s hospitals – Children’s National Health System, Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Medical Center – funded by an R01 grant to study how electronic health records can detect and identify novel markers of severe growth disorders.

The researchers hope their findings will also identify and help screen for comorbidities associated with atypical growth patterns, supporting multidisciplinary treatment throughout a child’s life. The study started in August 2018 and includes three sets of unique diagnostic criteria and will analyze WES from dozens of patients over five years.

Read more about Dr. Dauber’s research presented at ENDO 2019 in Endocrine Today and watch his video commentary with Medscape.

Nichole Jefferson and Patrick Gee

African American stakeholders help to perfect the APOLLO study

Nichole Jefferson and Patrick Gee

Nichole Jefferson and Patrick O. Gee

African Americans who either donated a kidney, received a kidney donation, are on dialysis awaiting a kidney transplant or have a close relative in one of those categories are helping to perfect a new study that aims to improve outcomes after kidney transplantation.

The study is called APOLLO, short for APOL1 Long-Term Kidney Transplantation Outcomes Network. Soon, the observational study will begin to enroll people who access transplant centers around the nation to genotype deceased and living African American kidney donors and transplant recipients to assess whether they carry a high-risk APOL1 gene variant.

The study’s Community Advisory Council – African American stakeholders who know the ins and outs of kidney donation, transplantation and dialysis because they’ve either given or  received an organ or are awaiting transplant – are opening the eyes of researchers about the unique views of patients and families.

Already, they’ve sensitized researchers that patients may not be at the same academic level as their clinicians, underscoring the importance of informed consent language that is understandable, approachable and respectful so people aren’t overwhelmed. They have encouraged the use of images and color to explain the apolipoprotein L1 (APOL1) gene. The APOL1 gene is found almost exclusively in people of recent African descent, however only 13 percent of these people carry the high-risk APOL1 variant that might cause kidney problems.

One issue arose early, during one of the group’s first monthly meetings, as they discussed when to tell patients and living donors about the APOLLO study. Someone suggested the day of the transplant.

“The Community Advisory Council told them that would not be appropriate. These conversations should occur well before the day of the transplant,” recalls Nichole Jefferson.

“The person is all ready to give a kidney. If you’re told the day of transplant ‘we’re going to include you in this study,’ that could possibly stop them from giving the organ,” Jefferson says. “We still remember the Tuskegee experiments. We still remember Henrietta Lacks. That is what we are trying to avoid.”

Patrick O. Gee, Ph.D., JLC, another Community Advisory Council member, adds that it’s important to consider “the mental state of the patient and the donor. As a patient, you know you are able to endure a five- to eight-hour surgery. The donor is the recipient’s hero. As the donor, you want to do what is right. But if you get this information; it’s going to cause doubt.”

Gee received his kidney transplant on April 21, 2017, and spent 33 days in the hospital undergoing four surgeries. His new kidney took 47 days to wake up, which he describes as a “very interesting journey.” Jefferson received her first transplant on June 12, 2008. Because that kidney is in failure, she is on the wait list for a new kidney.

“All I’ve ever known before APOLLO was diabetes and cardiovascular issues. Nobody had ever talked about genetics,” Gee adds. “When I tell people, I tread very light. I try to stay in my lane and not to come off as a researcher or a scientist. I just find out information and just share it with them.”

As he spoke during a church function, people began to search for information on their smart phones. He jotted down questions “above his pay grade” to refer to the study’s principal investigator. “When you start talking about genetics and a mutated gene, people really want to find out. That was probably one of the best things I liked about this committee: It allows you to learn, so you can pass it on.”

Jefferson’s encounters are more unstructured, informing people who she meets about her situation and kidney disease. When she traveled from her Des Moines, Iowa, home to Nebraska for a transplant evaluation, the nephrologist there was not aware of the APOL1 gene.

And during a meeting at the Mayo Clinic with a possible living donor, she asked if they would test for the APOL1 gene. “They stopped, looked at me and asked: ‘How do you know about that gene?’ Well, I’m a black woman with kidney failure.”

Patrick O. Gee received his kidney transplant on April 21, 2017, and spent 33 days in the hospital undergoing four surgeries. His new kidney took 47 days to wake up, which he describes as a “very interesting journey.”

About 100,000 U.S. children and adults await a kidney transplant. APOLLO study researchers believe that clarifying the role that the APOL1 gene plays in kidney-transplant failure could lead to fewer discarded kidneys, which could boost the number of available kidneys for patients awaiting transplant.

Gee advocates for other patients and families to volunteer to join the APOLLO Community Advisory Council. He’s still impressed that during the very first in-person gathering, all researchers were asked to leave the table. Only patients and families remained.

“They wanted to hear our voices. You rarely find that level of patient engagement. Normally, you sit there and listen to conversations that are over your head. They have definitely kept us engaged,” he says. “We have spoken the truth, and Dr. Kimmel is forever saying ‘who would want to listen to me about a genotype that doesn’t affect me? We want to hear your voice.’ ”

(Paul L. Kimmel, M.D., MACP, a program director at the National Institute of Diabetes and Digestive and Kidney Diseases, is one of the people overseeing the APOLLO study.)

Jefferson encourages other people personally impacted by kidney disease to participate in the APOLLO study.

“Something Dr. Kimmel always says is ‘You’re in the room.’ We’re in the room while it’s happening. It’s a line from Hamilton. That’s a good feeling,” she says. “I knew right off, these are not necessarily improvements I will see in my lifetime. I am OK with that. With kidney disease, we have not had advances in a long time. As long as my descendants don’t have to go through the same things I have gone through, I figure I have done my part. I have done my job.”

Zhe Han lab 2018

$2 million NIH grant to study nephrotic syndrome

Zhe Han lab 2018

A Children’s researcher has received a $2 million grant from the National Institutes of Health (NIH) to study nephrotic syndrome in Drosophila, a basic model system that has revealed groundbreaking insights into human health. The award for Zhe Han, Ph.D., an associate professor in Children’s Center for Genetic Medicine Research, is believed to be the first ever NIH Research Project grant (R01)  to investigate glomerular kidney disease using Drosophila. Nephrotic syndrome is mostly caused by damage of glomeruli, so it is equivalent to glomerular kidney disease.

“Children’s National leads the world in using Drosophila to model human kidney diseases,” Han says.

In order to qualify for the five-year funding renewal, Han’s lab needed to successfully accomplish the aims of its first five years of NIH funding.  During the first phase of funding, Han established that nephrocytes in Drosophila serve the same functions as glomeruli in humans, and his lab created a series of fly models that are relevant for human glomerular disease.

“Some 85 percent of the genes known to be involved in nephrotic syndrome are conserved from the fly to humans. They play similar roles in the nephrocyte as they play in the podocytes in human kidneys,” he adds.

Pediatric nephrotic syndrome is a constellation of symptoms that indicate when children’s kidneys are damaged, especially the glomeruli, units within the kidney that filter blood. Babies as young as 1 year old can suffer proteinuria, which is characterized by too much protein being released from the blood into the urine.

“It’s a serious disease and can be triggered by environmental factors, taking certain prescription medicines or inflammation, among other factors.  Right now, that type of nephrotic syndrome is mainly treated by steroids, and the steroid treatment works in many cases,” he says.

However, steroid-resistant nephrotic syndrome occurs primarily due to genetic mutations that affect the kidney’s filtration system: These filters are either broken or the protein reabsorption mechanism is disrupted.

“When genetics is to blame, we cannot turn to steroids. Right now there is no treatment. And many of these children are too young to be considered for a kidney transplant,” he adds. “We have to understand exactly which genetic mutation caused the disease in order to develop a targeted treatment.”

With the new funding, Han will examine a large array of genetic mutations that cause nephrotic syndrome. He’s focusing his efforts on genes involved in the cytoskeleton, a network of filaments and tubules in the cytoplasm of living cells that help them to maintain shape and carry out important functions.

“Right now, we don’t really understand the cytoskeleton of podocytes – highly specialized cells that wrap around the capillaries of the glomerulus – because podocytes are difficult to access. To change a gene requires time and considerable effort in other experimental models. However, changing genes in Drosophila is very easy, quick and inexpensive. We can examine hundreds of genes involving the cytoskeleton and see how changing those genes affect kidney cell function,” he says.

Han’s lab already found that Coenzyme Q10, one of the best-selling nutrient supplements to support heart health also could be beneficial for kidney health. For the cytoskeleton, he has a different targeted medicine in mind to determine whether Rho inhibitors also could be beneficial for kidney health for patients with certain genetic mutations affecting their podocyte cytoskeleton.

“One particular aim of our research is to use the same strategy as we employed for the Coq2 gene to generate a personalized fly model for patients with cytoskeleton gene mutations and test potential target drugs, such as Rho inhibitors.” Han added. “As far as I understand, this is where the future of medicine is headed.”

DNA Molecule

Test your knowledge of APOL1’s role in kidney health

Zhe Han

$3 million NIH grant to study APOL1 and HIV synergy

Zhe Han

Zhe Han, Ph.D., (pictured) and Patricio E. Ray, M.D., have received a $3 million, five-year grant from the National Institutes of Health to study the mechanisms behind APOL1 and HIV nephropathies in children, using a combination of Drosophila models, cultured human podocytes and a preclinical model.

Two Children’s researchers have received a $3 million, five-year grant from the National Institutes of Health (NIH) to study the mechanisms of APOL1 and HIV nephropathies in children, using a combination of Drosophila models, cultured human podocytes and a preclinical model.

The APOL1 genetic variants G1 and G2, found almost exclusively in people of African ancestry, lead to a four-fold higher risk of end-stage kidney disease. HIV infection alone also increases the risk of kidney disease but not significantly. However, HIV-positive people who also carry the APOL1 risk alleles G1 or G2 are about 30 times more likely to develop HIV-nephropathy (HIVAN) and chronic kidney disease.

For more than 25 years, Children’s pediatric nephrology program has studied HIV/renal diseases and recently developed Drosophila APOL1-G0 and G1 transgenic lines. That pioneering research suggests that HIV-1 acts as a “second hit,” precipitating HIV-renal disease in children by infecting podocytes through a mechanism that increases expression of the APOL1-RA beyond toxic thresholds.

With this new infusion of NIH funding, labs led by Zhe Han, Ph.D., and Patricio E. Ray, M.D., will determine the phenotype of Drosophila Tg lines that express APOL1-G0/G1/G2 and four HIV genes in nephrocytes to assess how they affect structure and function. The teams also will determine whether APOL1-RA precipitates the death of nephrocytes expressing HIV genes by affecting autophagic flux.

“Our work will close a critical gap in understanding about how HIV-1 interacts with the APOL1 risk variants in renal cells to trigger chronic kidney disease, and we will develop the first APOL1/HIV transgenic fly model to explore these genetic interactions in order to screen new drugs to treat these renal diseases,” says Dr. Ray, a Children’s nephrologist.

While a large number of people from Africa have two copies of APOL1 risk alleles, they do not necessarily develop kidney disease. However, if a patient has two copies of APOL1 risk alleles and is HIV-positive, they almost certainly will develop kidney disease.

Patricio Ray

“Our work will close a critical gap in understanding about how HIV-1 interacts with the APOL1 risk variants in renal cells to trigger chronic kidney disease, and we will develop the first APOL1/HIV transgenic fly model to explore these genetic interactions in order to screen new drugs to treat these renal diseases,” says Dr. Ray, a Children’s nephrologist.

“Many teams want to solve the puzzle of how APOL1 and HIV synergize to cause kidney failure,” says Han, associate professor in Children’s Center for Genetic Medicine Research. “We are in the unique position of combining a powerful new kidney disease model system, Drosophila, with long-standing human podocyte and HIVAN studies.”

The team hypothesizes that even as an active HIV infection is held in check by powerful new medicines, preventing the virus from proliferating or infecting new cells, HIV can act as a Trojan horse by making the human cells it infects express HIV protein.

To investigate this hypothesis, the team will create a series of fly models, each expressing a major HIV protein, and will test the genetic interaction between these HIV genes with APOL1. Similar studies also will be performed using cultured human podocytes. Identified synergy will be studied further using biochemical and transcription profile analyses.

Drosophila is a basic model system, but it has been used to make fundamental discoveries, including genetic control of how the body axes is determined and how the biological clock works – two studies that led to Nobel prizes,” Han adds. “I want to use the fly model to do something close to human disease. That is where my research passion lies.”

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Vittorio Gallo

Neurodevelopmental disorders: Developing medical treatments

Vittorio Gallo

Vittorio Gallo, Ph.D., Chief Research Officer, participates in the world’s largest general scientific gathering, leading panelists in a timely conversation about progress made so far with neurodevelopmental disorders and challenges that lie ahead.

The human brain is the body’s operating system. Imagine if rogue code worked its way into its hardware and software, delaying some processes, disrupting others, wreaking general havoc.

Neurodevelopmental disorders are like that errant code. They can occur early in life and impact brain development for the rest of the person’s life. Not only can fundamental brain development go awry, processes that refine the brain also can become abnormal, creating a double neural hit.  Adding to those complications, children with neurodevelopmental disorders like autism spectrum disorder (ASD) and Fragile X syndrome often contend with multiple, overlapping cognitive impairments and learning disabilities.

The multiple layers of complexities for these disorders can make developing effective medical treatments particularly challenging, says Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National Health System and recipient of a coveted Senator Jacob Javits Award in the Neurosciences.

During the Feb. 16, 2019, “Neurodevelopmental Disorders: Developing Medical Treatments” symposium, Gallo will guide esteemed panelists in a timely conversation about progress made so far and challenges that lie ahead during the AAAS Annual Meeting in Washington, the world’s largest general scientific gathering.

“This is a very important symposium; we’re going to put all of the open questions on the table,” says Gallo. “We’re going to present a snapshot of where the field is right now: We’ve made incredible advances in developmental neuroscience, neonatology, neurology, diagnostic imaging and other related fields. The essential building blocks are in place. Where are we now in developing therapeutics for these complex disorders?”

For select disorders, many genes have been identified, and each new gene has the potential to become a target for improved therapies. However, for other neurodevelopmental disorders, like ASD, an array of new genes continue to be discovered, leaving an unfinished picture of which genetic networks are of most importance.

Gallo says the assembled experts also plan to explore major research questions that remain unanswered as well as how to learn from past experiences to make future studies more powerful and insightful.

“One topic up for discussion will be new preclinical models that have the potential to help in identifying specific mechanisms that cause these disorders. A combination of genetic, biological, psychosocial and environmental risk factors are being combined in these preclinical models,” Gallo says.

“Our studies of the future need to move beyond describing and observing in order to transform into studies that establish causality between the aberrant developmental processes and these constellations of neurodevelopmental disorders.”

dystrophin protein

Experimental drug shows promise for slowing cardiac disease and inflammation

dystrophin protein

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein found mostly in skeletal, respiratory and heart muscles.

Vamorolone, an experimental medicine under development, appears to combine the beneficial effects of prednisone and eplerenone – standard treatments for Duchenne muscular dystrophy (DMD) – in the heart and muscles, while also showing improved safety in experimental models. The drug does so by simultaneously targeting two nuclear receptors important in regulating inflammation and cardiomyopathy, indicates a small study published online Feb. 11, 2019, in Life Science Alliance.

DMD is a progressive X-linked disease that occurs mostly in males. It is characterized by muscle weakness that worsens over time, and most kids with DMD will use wheelchairs by the time they’re teenagers. DMD is caused by mutations in the DMD gene, which provides instructions for making dystrophin, a protein found mostly in skeletal, respiratory and heart muscles.

Cardiomyopathy, an umbrella term for diseases that weaken the heart, is a leading cause of death for young adults with DMD, causing up to 50 percent of deaths in patients who lack dystrophin. A collaborative research team co-led by Christopher R. Heier, Ph.D., and Christopher F. Spurney, M.D., of Children’s National Health System, is investigating cardiomyopathy in DMD. They find genetic dystrophin loss provides “a second hit” for a specific pathway that worsens cardiomyopathy in experimental models of DMD.

“Some drugs can interact with both the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) since these two drug targets evolved from a common ancestor. However, we find these two drug targets can play distinctly different roles in heart and skeletal muscle. The GR regulates muscle inflammation, while the MR plays a key role in heart health,” says Heier, an assistant professor at Children’s National and lead study author. “In our study, the experimental drug vamorolone safely targets both the GR to treat chronic inflammation and the MR to treat the heart.”

After gauging the efficacy of various treatments in test tubes, the study team looked at whether any could mitigate negative impacts of the MR on heart health. Wild type and mdx experimental models were implanted with pumps that activated the MR. These models also received a daily oral MR antagonist (or inhibitor) drug, and either eplerenone, spironolactone or vamorolone. Of note:

  • MR activation increased kidney size and caused elevated blood pressure (hypertension).
  • Treatment with vamorolone maintained normal kidney size and prevented hypertension.
  • MR activation increased mdx heart mass and fibrosis. Vamorolone mitigated these changes.
  • MR activation decreased mdx heart function, while vamorolone prevented declines in function.
  • Daily prednisone caused negative MR- and GR-mediated side effects, such as hyperinsulinemia, whereas vamorolone safely improved heart function without these side effects.

“These findings have the potential to help current and future patients,” Heier says. “Clinicians already prescribe several of these drugs. Our new data support the use of MR antagonists such as eplerenone in protecting DMD hearts, particularly if patients take prednisone. The experimental drug vamorolone is currently in Phase IIb clinical trials and is particularly exciting for its unique potential to simultaneously treat chronic inflammation and heart pathology with improved safety.”

In addition to Heier and senior author Spurney, study co-authors include Qing Yu, Alyson A. Fiorillo, Christopher B. Tully, Asya Tucker and Davi A. Mazala, all of Children’s National; Kitipong Uaesoontrachoon and Sadish Srinivassane, AGADA Biosciences Inc.; and Jesse M. Damsker, Eric P. Hoffman and Kanneboyina Nagaraju, ReveraGen BioPharma.

Financial support for research described in this report was provided by Action Duchenne; the Clark Charitable Foundation; the Department of Defense under award W81XWH-17-1-047; the Foundation to Eradicate Duchenne; the Intellectual and Developmental Disabilities Research Center under award U54HD090257 (through the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development); and the NIH under awards K99HL130035, R00HL130035, L40AR068727 and T32AR056993.

Financial disclosure:  Co-authors employed by ReveraGen BioPharma were involved in creating this news release.

mitochondria

Treating nephrotic-range proteinuria with tacrolimus in MTP

mitochondria

Mitochondria are the cell’s powerplants and inside them the MTP enzymatic complex catalyzes three steps in beta-oxidation of long-chain fatty acids.

In one family, genetic lightning struck twice. Two sisters were diagnosed with mitochondrial trifunctional protein (MTP) deficiency. This is a rare condition that stops the body from converting fats to energy, which can lead to lactic acidosis, recurrent breakdown of muscle tissue and release into the bloodstream (rhabdomyolysis), enlarged heart (cardiomyopathy) and liver failure.

Mitochondria are the cell’s powerplants and inside them the MTP enzymatic complex catalyzes three steps in beta-oxidation of long-chain fatty acids. MTP deficiency is so rare that fewer than 100 cases have been reported in the literature says Hostensia Beng, M.D., who presented an MTP case study during the American Society of Nephrology’s Kidney Week.

The 7-month-old girl with known MTP deficiency arrived at Children’s National lethargic with poor appetite. Her laboratory results showed a low corrected serum calcium level, elevated CK level and protein in the urine (proteinuria) at a nephrotic range. The infant was treated for primary hypoparathyroidism and rhabdomyolysis.

Even though the rhabdomyolysis got better, the excess protein in the girl’s urine remained at worrisome levels. A renal biopsy showed minimal change disease and foot process fusion. And electron microscopy revealed shrunken, dense mitochondria in visceral epithelial cells and endothelium.

“We gave her tacrolimus, a calcineurin inhibitor that we are well familiar with because we use it after transplants to ensure patient’s bodies don’t reject the donated organ. By eight months after treatment, the girl’s urine protein-to-creatinine (uPCR) ratio was back to normal. At 35 months, that key uPCR measure rose again when tacrolimus was discontinued. When treatment began again, uPCR was restored to normal levels one month later,” Dr. Beng says.

The girl’s older sister also shares the heterozygous deletion in the HADHB gene, which provides instructions for making MTP. That missing section of the genetic how-to guide was predicted to cause truncation and loss of long-chain-3-hydroxyacl CoA dehydrogenase function leading to MTP deficiency.

The older sister was diagnosed with nephrotic syndrome and having scar tissue in the kidney’s filtering unit (focal segmental glomerulosclerosis) when she was 18 months old. By contrast, she developed renal failure and progressed to end stage renal disease at 20 months of age.

“Renal involvement has been reported in only one patient with MTP deficiency to date, the older sister of our patient,” Dr. Beng adds.

Podocytes are specialized cells in the kidneys that provide a barrier, preventing plasma proteins from leaking into the urine. Podocytes, however, need energy to function and are rich in mitochondria.

“The proteinuria in these two sisters may be related to their mitochondrial dysfunction. Calcineurin inhibitors like tacrolimus have been reported to reduce proteinuria by stabilizing the podocyte actin cytoskeleton. Tacrolimus was an effective treatment for our patient, who has maintained normal renal function, unlike her sister,” Dr. Beng says.

American Society of Nephrology’s Kidney Week presentation

  • “Treatment of nephrotic-range proteinuria with tacrolimus in mitochondrial trifunctional protein deficiency

Hostensia Beng, M.D., lead author; Asha Moudgil, M.D., medical director, transplant, and co-author; Sun-Young Ahn, M.D., MS, medical director, nephrology inpatient services, and senior author, all of Children’s National Health System.

little girl with spina bifida

Oral clefts may stem from a shared genetic cause as neural tube defects

little girl with spina bifida

Research by an international team that includes Children’s National faculty, published online Jan. 25, 2019 in Human Molecular Genetics, suggests that genetic mutations that cause cleft lip and palate also may contribute to neural tube defects, such as spina bifida.

Oral clefts are some of the most common birth defects worldwide, affecting about one in every 700 births. In the U.S., more than 4,000 babies are born each year with cleft lip, with or without cleft palate.

This defect isn’t simply a cosmetic manner: Oral clefts can severely affect feeding, speech and hearing, and they cause about 3,300 deaths annually worldwide.

To better understand these conditions, researchers have isolated a number of genetic mutations that appear to play contributing roles. These include those in a gene known as Interferon Regulatory Factor 6. New research by an international team that includes Children’s National faculty, published online Jan. 25, 2019 in Human Molecular Genetics, suggests that these mutations also may contribute to neural tube defects such as spina bifida.

In the first weeks of fetal development, the neural plate curves, creating a neural tube that, once fused shut, becomes the fetal brain and fetal spinal cord. Neural tube defects, which can range from mild to severe, are characterized by incomplete development of the brain, spinal cord or meninges. These defects can potentially result in paralysis or even fetal or neonatal demise. According to the National Institutes of Health, spina bifida, which affects the spinal cord, is the most common neural tube defect in the U.S., affecting up to 2,000 infants each year.

“Despite its high frequency, spina bifida remains among the least understood structural birth defects,” says Brian C. Schutte, an associate professor of Microbiology and Molecular Genetics, Pediatrics and Human Development at Michigan State University and the study’s senior author. “There is strong evidence that genetic factors are a leading cause of such structural birth defects, but in most cases, the cause is unknown. Our team’s study is the first published research to demonstrate that DNA variants in the gene IRF6 can cause spina bifida,” Schutte says.

What’s more, the research team identified a mechanism to explain how altering IRF6 leads to neural tube defects. This mechanism links IRF6 function to two other genes – known as transcription Factor AP2A (TFAP2A) and Grainyhead Like 3 (GRHL3) – that are also known to be required for the development of the neural tube, lip and palate.

“We’re all on the hunt for the reasons when, how and why birth defects happen,” adds Youssef A. Kousa, MS, D.O., Ph.D., a clinical fellow in the Division of Child Neurology at Children’s National Health System and the study’s lead author. “Our main goal is prevention. This paper is a significant development because our team has identified a group of genes that can potentially contribute to very common types of birth defects: craniofacial as well as neural tube defects.”

The scientific odyssey is a wonderful example of serendipity. Kousa, then working in Schutte’s lab, was studying the effects of a new mutant experimental model strain on development of the palate. But one day, he walked into Schutte’s office holding a deformed preclinical embryo and said: “Brian, look at this!”

“Weird things happen in biology,” Schutte replied and counseled him to return if it happened again. Less than two weeks later, Kousa was back with several more of the deformed preclinical embryos, saying: “OK, Brian. It happened again.”

Within hours Kousa had unearthed recently published research that included an image of a similarly affected preclinical embryo. The pair then sketched out possible intersecting genetic pathways, as they brainstormed the myriad ways to end up with that specific phenotype. Initially, they tested their hypotheses in experimental models and eventually corroborated findings through human genetic studies.

The human studies could only be performed by collaborations. Schutte shared their initial observations with human genetics researchers scattered across the country. Those labs then generously agreed to test whether DNA variants in IRF6 were associated with neural tube defects in samples from patients that they had collected over decades of research.

The team found that Tfap2aIrf6 and Grhl3 are components of a gene regulatory network required for neurulation, a folding process that results in the neural tube bending and then fusing to become the basis of the embryo’s nervous system, from brain to spinal cord.

“Since this network is also required for formation of the lip, palate, limbs and epidermis, which develop at different times and places during embryogenesis, we suggest that the Tfap2aIrf6Grhl3 network is a fundamental pathway for multiple morphogenetic processes,” the researchers write.

Interferon Regulatory Factor 6 functions best when there is neither too much expression nor too little. Overexpression of Irf6 suppresses Transcription Factor Activation Protein 2A and Grainyhead Like 3, causing exencephaly, a neural tube defect characterized by the brain being located outside of the skull. Counterintuitively, experimental models that had too little Irf6 also ended up with reduced levels of Tfap2a and Grhl3 that led to a structural birth defect, but at the opposite end of the neural tube.

To test whether the experimental model findings held true in humans, they sequenced samples from people who had spina bifida and anencephaly – the rare birth defect that Kousa spotted in the experimental models – and found IRF6 function was conserved in people. Because of the genetic complexity of these birth defects, and the challenges inherent in collecting samples from cases of severe birth defects, many research teams were invited to participate in the study.

As testament to their collegiality, researchers from Stanford University, University of Texas at Austin, University of Iowa, University of Texas at Houston and Duke University agreed to share precious samples from the California Birth Defects Monitoring Program, from the Hereditary Basis of Neural Tube Defects study and from their own institutional sample collections.

“As we get better at personalized medicine, we could use this information to one day help to counsel families about their own risk and protective factors,” Kousa adds. “If we can identify the genetic pathway, we might also be able to modify it to prevent a birth defect. For example, prenatal supplementation with folic acid has led to a decrease in babies born with neural tube defects, but not all neural tube defects are sensitive to folic acid. This knowledge will help us develop individual-based interventions.”

Financial support for the research covered in this post was provided by the National Institutes of Health under grants DE13513, F31DE022696, DE025060, P01HD067244 and GM072859; startup funding from Michigan State University and the UT-Health School of Dentistry in Houston; and the Centers for Disease Control and Prevention under award number 5U01DD001033.

In addition to Kousa and Schutte, study co-authors include Huiping Zhu, Yunping Lei and Richard H. Finnell, University of Texas at Austin; Walid D. Fakhouri, University of Texas Health Science Center at Houston; Akira Kinoshita, Nagasaki University; Raeuf R. Roushangar, Nicole K. Patel, Tamer Mansour, Arianna L. Smith, and Dhruv B. Sharma, Michigan State University; A.J. Agopian and Laura E. Mitchell, University of Texas School of Public Health; Wei Yang and Gary M. Shaw, Stanford University School of Medicine; Elizabeth J. Leslie, Emory University; Xiao Li, Tamara D. Busch, Alexander G. Bassuk and Brad A. Amendt, University of Iowa; Edward B. Li and Eric C. Liao, Massachusetts General Hospital; Trevor J. Williams, University of Colorado Denver at Anschutz Medical Campus; Yang Chai, University of Southern California; and Simon Gregory and Allison Ashley-Koch, Duke University Medical Center.

Pedbot video game

Pedbot’s next step – Home-based therapy

Pedbot video game

Pedbot’s home version adapts the same airplane-themed video game to a smaller therapeutic platform that is more affordable to build.

The novel ankle rehabilitation robot built at Children’s National to help children with cerebral palsy build ankle strength and control through video gaming is taking a big step forward. Engineers have created a smaller, more affordable version of the robotic platform using 3D printed parts, to explore the effectiveness of a home-based therapy program.

“We’re seeing preliminary success in our trial for in clinic use of the Pedbot. Now we’re hoping to see if making the technology accessible at home means that 1) Kids use it more often and 2) More frequent, regular use over time leads to better range of motion,” says Kevin Cleary, Ph.D., the Sheikh Zayed Institute for Pediatric Surgical Innovation’s bioengineering technical director and engineering lead for Pedbot.

Pedbot’s video game, designed by software engineer Hadi Fooladi, M.S., allows kids to pilot an airplane through a series of hoops at varying speeds as determined by the therapist and programmer. The game isn’t the only thing that’s unique about this therapeutic robot, however.

Just like the clinic version, the home model moves in three translational directions (x, y and z) and rotates about three axes (the x, y and z axes), similar to the movement of a flight simulator. The result is a robot that helps the patient exercise across a greater range of motion and build muscle strength in a way that more closely mimics real-life ankle function.

Pedbot Home potentially eliminates an additional major therapeutic barrier – the clinic appointment.

“The great thing about Pedbot is you’re constantly working to reach a moving target, and the therapist can vary the movement type as much or as little as needed for each patient,” says Catherine Coley, DPT, a physical therapist at Children’s National who is a member of the Pedbot development team. “We think the home version might make it easier for the child to succeed with a long term therapy program by removing the need for repeat clinic visits.”

“What if a child could come home from school and do their therapy at home after dinner? Would doing it every day for 20 minutes benefit the child more than just coming to see us once or twice a week for an hour? Can we make it easier for our patients to cooperate and follow through with therapy homework? These are some of the questions that we hope we can answer during our trial for the home version,” says Sally Evans, M.D., division chief of Pediatric Rehabilitation Medicine at Children’s National and clinical lead for the project.

The cross-functional Pedbot team includes engineers Reza Monfaredi Ph.D. and Tyler Salvador, B.S., as well as additional physical therapists, Stacey Kovelman, P.T. and Justine Belchner, P.T., and Sara Alyamani, B.A. Future expansions will include the addition of electromyography measurements in collaboration with Paola Pergami, M.D., Ph.D. and incorporation of other patient populations with Beth Wells, M.D.

Pedbot Home is currently being piloted in the home setting, with the goal of enrolling additional families to participate in a trial within the next year. The work is supported by a $500,000 federal grant from the Department of Health and Human Services’ National Institute on Disability, Independent Living, and Rehabilitation Research.