Genetics and Rare Diseases

Eric Vilain explores “Disorders/differences of sex development: A world of uncertainty”

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Eric Vilain

In his keynote address at Children’s National’s Research and Education Week, Eric Vilain, M.D., Ph.D., explored the genetics of sex development and sex differences.

After announcing he would be joining Children’s National as the new director of the Center for Genetic Medicine Research late last year, internationally-renowned geneticist Eric Vilain, M.D., Ph.D., gave a keynote address entitled “Disorders/Differences of Sex Development: A World of Uncertainty” during Children’s National’s Research and Education Week.

Dr. Vilain explored the genetics of sex development and sex differences – specifically differences of sex development (DSD), congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical.

“The first step in sex development is looking at genetic sex and how it results in gonadal sex,” Dr. Vilain said. “From a scientific perspective, we are trying to take a step back and assess how cells become more typically male or female.”

He explained that, at conception, the fundamental difference between male and female embryos exists in the sex chromosome complement. Both XX and XY embryos have bipotential gonads capable of differentiating into a testis or an ovary, though embryos are virtually indistinguishable from a gender perspective up until six weeks in utero.

Eric Vilain - sex differences

According to Dr. Vilain, the fundamental difference between male and female embryos exists in the sex chromosome complement, though embryos are virtually indistinguishable until six weeks in utero.

Whether or not a bipotential gonad forms is largely left up to the genetic makeup of the individual. For example, a gene in the Y chromosome (SRY) triggers a cascade of genes that lead to testis development. If there is no Y chromosome, it triggers a series of pro-female genes that lead to ovarian development.

However, genetic mutations can alter the subsequent steps of sex differentiation. Dr. Vilain explained that, depending on the genotype, an individual may experience normal gonadal development, but abnormal development of the genitalia.

He also noted that these genes are critical to determining the differences between men and women in non-gonadal tissues as well.

In addition to exploring the genetics of sex development and sex differences, Dr. Vilain’s research explores the biological bases of sex variations in predisposition to disease. His clinic at Children’s National is completely devoted to caring for patients with a wide array of genetic and endocrine issues, particularly cases dealing with variations of sex development.

For seven years, Children’s National’s Research and Education Week has celebrated the excellence in research, education, innovation and scholarship at Children’s National and around the world. This year, the annual event focused how “Collaboration Leads to Innovation” and celebrated the development of ideas that aim to transform pediatric care.

Irf6

IRF6 gene plays roles in tissue development beyond epithelium

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Irf6

Kousa, Y. A., Moussa, D. and Schutte, B. C. (2017), IRF6 expression in basal epithelium partially rescues Irf6 knockout mice. Developmental Dynamics, 2017. © 2017 Wiley Periodicals, Inc.

PDF Version

What’s known

IRF6 is a gene that plays a key role in the development of epithelium, the tissue that lines the cavities and surfaces of blood vessels and organs throughout the body. Mutations in this gene are known to contribute to human diseases, including van der Woude syndrome and popliteal pterygium syndrome, both of which are characterized by cleft lip and palate, skin abnormalities and limb defects. Experimental models that are genetically modified to lack this gene typically have systemic defects so severe that they die at birth. However, it’s been unclear whether these defects are all due to problems with the epithelium and their related consequences, or if IRF6 also plays a role in other tissues during fetal development.

What’s new

A research team led by Youssef A. Kousa, M.S., D.O., Ph.D., a pediatric resident in the child neurology track at Children’s National Health System, investigated where IRF6’s activity is important by partially “rescuing” experimental models altered to lack this gene – or selectively restoring its activity – in just the epithelium. When the resulting animals were born, they survived for hours, unlike animals that lack IRF6 completely. However, the partially rescued experimental models had physical characteristics that were intermediate between animals that were not genetically modified and those that totally lacked IRF6. These partially rescued animals still had cleft palates, skin abnormalities and limb defects, but these defects were not as severe as the modified animals that weren’t rescued at all. The findings suggest that IRF6 plays a role in development of tissue types beyond epithelium. Gaining a better understanding of how mutations in this gene exert their effects on this array of tissues eventually may help researchers develop ways to prevent related disorders or to treat them early in development.

Questions for future research

Q: What function is IRF6 playing in tissues beyond epithelium?
Q: Which defects lead to premature death in experimental models whose IRF6 function is restored in the epithelium?
Q: Is there a way to prevent defects caused by IRF6 mutations without the need to restore IRF6 function directly?

Source: “IRF6 expression in basal epithelium partially rescues Irf6 knockout mice.” Kousa, Y.A., D. Moussa and B.C. Schutte. Published online by Developmental Dynamics June 23, 2017.
Youssef A. Kousa

Generating a conditional allele of Irf6

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Youssef A. Kousa

A research team that includes Youssef A. Kousa, M.S., D.O., Ph.D., has created a novel tool to delete Interferon regulatory factor 6, which regulates how epidermal cells differentiate, multiply and migrate.

A research team has created a novel tool to delete Interferon regulatory factor 6 (Irf6), which regulates how epidermal cells differentiate, multiply and migrate.

Mutations of this critical transcription factor are implicated in two orofacial clefting disorders. As with other transcription factors, the IRF6 protein binds to specific regions of DNA and plays a role in that specific gene’s activity. With van der Woude syndrome, a rare disease that occurs in 1 in 35,000 individuals, the National Institutes of Health (NIH) says mutations to the IRF6 gene inhibit production of the IRF6 protein. That protein shortfall lies at the heart of incomplete development and stalled maturation of tissues in the skull and face. For popliteal pterygium syndrome, IRF6 mutations can trigger facial abnormalities, webbed skin, and fused fingers and toes.

According to the NIH, the IRF6 protein is active in embryonic skin cells that later become tissue in the head, face and tongue. The study authors write that DNA variation in the IRF6 gene (which issues the marching orders to make the IRF6 protein) significantly heightens risk for developing non-syndromic cleft lip and palate, one of the most common congenital defects.

Studying the function of this critical gene in preclinical models has been hobbled by the fact that experimental models created without the Irf6 allele are born with severe skin, limb and craniofacial defects and die shortly after birth.

To overcome this hurdle, the research team did a bit of creative genetic shuffling to make a conditional allele of Irf6 to test in specific tissues at specific times as the experimental animals matured.

“The experimental models with the Irf6 conditional allele were viable after birth and, in fact, showed no developmental or reproductive defects when compared with their litter mates – which provides a reassurance that this specific change does not appear to affect overall normal gene function,” says Youssef A. Kousa, M.S., D.O., Ph.D., a pediatric resident in the child neurology track at Children’s National Health System and co-lead author of the technology report published online May 8, 2017 in Genesis.

To drill down into how the conditional allele affected the experimental models, the research team bred them with other animals specially designed to illuminate the function of the conditional allele. Some genotypes were lost, as was expected. Litters that were hypothesized to experience certain rates of severe limb, skin and craniofacial abnormalities did so. Immunostaining revealed IRF6 expression throughout the spinous layer and basal ­­­– or deepest ­­­– layer of the epidermis, but such expression was lacking in wildtype and knockout embryos.

In a different group of experimental models, the researchers added the deleter strain Ella-Cre. Nineteen resulting embryos were positive for the conditional allele but showed no evidence of recombination. Eight normal embryos showed incomplete recombination.  Nine embryos showed complete recombination in tail tissue. Just one embryo phenocopied the wild type embryos.

“Our research team successfully created the conditional allele for IRF6, which will open the door to future studies of gene function in neonatal experimental models,” Dr. Kousa and colleagues conclude. “Even though the allele is capable of recombination, we saw that efficacy varied and is linked to specific cell types. One possible explanation is variation in chromatin structure at the IRF6 locus.”

Future research will explore the utility of other Cre-drivers, such as Gdf9-Cre or CAG-Cre, to provide additional clarity about the functionality of the newly derived conditional alleles.

Mark Batshaw

Gene therapy’s slow rebirth

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Mark Batshaw

A speech by outgoing American Pediatric Society President Mark L. Batshaw, M.D., explored the impact of a single clinical trial on the entire field.

Gene therapy – delivering genetic material into patients’ cells as a way to treat or cure their diseases – has immense promise to alleviate or end many lifelong and deadly conditions. This treatment has so much potential that it was a heavy focus of research and research dollars around the world in the 1980s and 1990s.

However, many of these efforts came to a screeching halt in 1999 when a teenaged patient named Jesse Gelsinger died in a gene therapy trial aimed at curing a disease called ornithine transcarbamylase deficiency, a urea cycle disorder. Gelsinger’s death triggered a number of investigations, halted gene therapy trials in the United States, and severely restricted financial support from federal, foundation and industry funders.

The tragedy also spurred Mark L. Batshaw, M.D., one of the clinical trial investigators and newly named Chief Academic Officer at Children’s National Health System, to turn in his resignation. The chief executive at the time declined to accept it, instead naming an outside panel to investigate Dr. Batshaw’s role in a study marred by conflicts of interest, delays in updating patient consent forms, lack of adherence to the study protocol and ineffective team leadership.

As Dr. Batshaw passed the gavel to the next president of the American Pediatric Society during the Pediatric Academic Societies’ annual meeting this spring, he told attendees of his Presidential Address that “not a day goes by that I don’t think of Jesse Gelsinger and his family and hope that the work our team has continued will honor him by eventually achieving success with gene therapy.” In an act of altruism, 18-year-old Jesse Gelsinger had joined the trial with the aim of helping other kids suffering from metabolic disorder.

Dr. Batshaw recognizes that his is an unusual choice, speaking about his “greatest professional failure” when predecessors have used their addresses to speak exclusively about scientific accomplishments.

“Because I was a principal, I think telling this story first of all says, hey look, this guy who is president of this organization, who has had a significant career, is willing to talk openly about a failure and how he dealt with it and how the field dealt with that failure,” Dr. Batshaw says. “Secondly, the field of gene therapy right now is starting to explode. It’s telling two different stories in an integrated way: One is of a great personal failure – and failure of an entire field. And the recovery from that, and what the future will be for a technology that holds great promise.”

More than 1,000 gene therapy trials are currently underway, 23 of them at Phase III, the pivotal stage that makes or breaks approval by the Food and Drug Administration (FDA). Dr. Batshaw estimates about a dozen of those are likely to demonstrate robust enough results to progress to a formal application for FDA approval. “After a period of virtually no growth in gene therapy trials from 2000 to 2013, there has been a marked upswing in the past two to three years,” he says.

Children’s National is a study site for one of those clinical trials, a Phase I/II adenoassociated virus (AAV)-mediated gene therapy for late-onset ornithine transcarbamylase (OTC) deficiency. Children with urea cycle disorders have enzyme deficiencies that leave them unable to adequately dispose of waste nitrogen. Often as newborns, they develop severely elevated ammonia in their brains leading to encephalopathy, an often fatal condition. The Phase I work will test escalating doses in three patients for safety. The Phase II work will explore whether the gene therapy improves outcomes like lowering ammonia levels and improving patients’ ability to convert ammonia to urea. (A precursor study in an experimental model was among the most impactful research papers published by Children’s National authors in 2016.)

“So, for both our group’s program – and viral-delivered gene therapy in general – there has been a rebirth after the disastrous outcome of the initial adenovirus trial in OTC deficiency,” Dr. Batshaw said in his prepared remarks. “This resurgence has likely been fueled by improved viral vectors, especially AAVs, and an improved economy and industry investment. The future of gene therapy is likely to be enhanced by new genetic therapy platforms including RNA interference as a means of vertically transmitted gene regulation and the CRISPR gene-editing technology. It will also be impacted by the results of the trials that will be completed in the next few years, especially those using AAV vectors in hemophilia A and B, spinal muscular atrophy and leukemia.”

Looking forward 10 years, Dr. Batshaw is hopeful that gene therapy will become part of the therapeutic tools routinely used to help patients who suffer from rare disease and cancer. Making that next leap forward will be powered by innovative research, including work by colleagues at Children’s National. Among the presenters at PAS2017, the world’s largest pediatric research meeting, were more than 100 Children’s presenters, speakers and moderators.

“It makes me very proud that there are so many clinicians who are also scientists who are not satisfied with simply doing things the way they have always been doing it but constantly questioning how can we do things better for our children?” Dr. Batshaw says. “Our whole focus at Children’s National is caring for children, and that means caring for them the very best way possible and not being satisfied with current therapy if it’s not curative.”

Facial analysis technology helps diagnose rare genetic disease

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Facial Analysis Technology

A new study uses facial analysis technology developed at Children’s National to diagnose 22q1.2 deletion syndrome, also known as DiGeorge syndrome.

According to a new study led by the National Human Genome Research Institute (NHGRI), facial analysis technology can assist clinicians in making accurate diagnosis of 22q1.2 deletion syndrome, also known as DiGeorge syndrome. Using objective facial analysis software, developed by researchers from the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, the study compared the most relevant facial features characteristic of DiGeorge syndrome in diverse populations. Based on a selection of 126 individual facial features, the researchers were able to correctly diagnose patients with the disease from different ethnic groups with 96.6 percent or higher accuracy.

“The results of the study demonstrated that the identification of rare diseases benefits from adapting to ethnic and geographic populations,” said Marius George Linguraru, D.Phil., developer of the facial analysis technology and an investigator in the study from Children’s National.

Linguraru and his team are also working on a simple tool that will enable doctors in clinics without state-of-the-art genetic facilities to take photos of their patients on a smartphone and receive instant results.

Coenzyme Q10

Supplement might help kidney disease

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Coenzyme Q10

A research team was able to “rescue” phenotypes caused by silencing the fly CoQ2 gene by providing nephrocytes with a normal human CoQ2 gene, as well as by providing flies with Q10, a popular supplement.

A new study led by Children’s National research scientists shows that coenzyme Q10 (CoQ10), a popular over-the-counter supplement sold for pennies a dose, could alleviate genetic problems that affect kidney function. The work, done in genetically modified fruit flies — a common model for human genetic diseases since people and fruit flies share a majority of genes — could give hope to human patients with problems in the same genetic pathway.

The new study, published April 20 by Journal of the American Society of Nephrology, focuses on genes the fly uses to create CoQ10.

“Transgenic Drosophila that carry mutations in this critical pathway are a clinically relevant model to shed light on the genetic mutations that underlie severe kidney disease in humans, and they could be instrumental for testing novel therapies for rare diseases, such as focal segmental glomerulosclerosis (FSGS), that currently lack treatment options,” says Zhe Han, Ph.D., principal investigator and associate professor in the Center for Cancer & Immunology Research at Children’s National and senior study author.

Nephrotic syndrome (NS) is a cluster of symptoms that signal kidney damage, including excess protein in the urine, low protein levels in blood, swelling and elevated cholesterol. The version of NS that is resistant to steroids is a major cause of end stage renal disease. Of the more than 40 genes that cause genetic kidney disease, the research team concentrated on mutations in genes involved in the biosynthesis of CoQ10, an important antioxidant that protects the cell against damage from reactive oxygen.

Drosophila pericardial nephrocytes perform renal cell functions including filtering of hemolymph (the fly’s version of blood), recycling of low molecular weight proteins and sequestration of filtered toxins. Nephrocytes closely resemble, in structure and function, the podocytes of the human kidney.  The research team tailor-made a Drosophila model to perform the first systematic in vivo study to assess the roles of CoQ10 pathway genes in renal cell health and kidney function.

One by one, they silenced the function of all CoQ genes in nephrocytes. If any individual gene’s function was silenced, fruit flies died prematurely. But silencing three specific genes in the pathway associated with NS in humans – Coq2, Coq6 and Coq8 – resulted in abnormal localization of slit diaphragm structures, the most important of the kidney’s three filtration layers; collapse of membrane channel networks surrounding the cell; and increased numbers of abnormal mitochondria with deformed inner membrane structure.

Journal of the American Society of Nephrology September 2017 cover

The flies also experienced a nearly three-fold increase in levels of reactive oxygen, which the study authors say is a sufficient degree of oxidative stress to cause cellular injury and to impair function – especially to the mitochondrial inner membrane. Cells rely on properly functioning mitochondria, the cell’s powerhouse, to convert energy from food into a useful form. Impaired mitochondrial structure is linked to pathogenic kidney disease.

The research team was able to “rescue” phenotypes caused by silencing the fly CoQ2 gene by providing nephrocytes with a normal human CoQ2 gene, as well as by providing flies with Q10, a readily available dietary supplement. Conversely, a mutant human CoQ2 gene from an patient with FSGS failed to rescue, providing evidence in support of that particular CoQ2 gene mutation causing the FSGS. The finding also indicated that the patient could benefit from Q10 supplementation.

“This represents a benchmark for precision medicine,” Han adds. “Our gene-replacement approach silenced the fly homolog in the tissue of interest – here, the kidney cells – and provided a human gene to supply the silenced function. When we use a human gene carrying a mutation from a patient for this assay, we can discover precisely how a specific mutation – in many cases only a single amino acid change – might lead to severe disease. We can then use this personalized fly model, carrying a patient-derived mutation, to perform drug testing and screening to find and test potential treatments. This is how I envision using the fruit fly to facilitate precision medicine.”

Related resources:
News release: Drosophila effectively models human genes responsible for genetic kidney diseases
Video: Using the Drosophila model to learn more about disease in humans

Drs. DeBiasi and du Plessis

Zika virus, one year later

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Drs. DeBiasi and du Plessis

A multidisciplinary team at Children’s National has consulted on 66 Zika-affected pregnancies and births since May 2016.

The first pregnant patient with worries about a possible Zika virus infection arrived at the Children’s National Health System Fetal Medicine Institute on Jan. 26, 2016, shortly after returning from international travel.

Sixteen months ago, the world was just beginning to learn how devastating the mosquito-borne illness could be to fetuses developing in utero. As the epidemic spread, a growing number of sun-splashed regions that harbor mosquitoes that efficiently spread the virus experienced a ballooning number of Zika-affected pregnancies and began to record sobering birth defects.

The Washington, D.C. patient’s concerns were well-founded. Exposure to Zika virus early in her pregnancy led to significant fetal brain abnormalities, and Zika virus lingered in the woman’s bloodstream months after the initial exposure — longer than the Centers for Disease Control and Prevention (CDC) then thought was possible.

The research paper describing the woman’s lengthy Zika infection, published by The New England Journal of Medicine, was selected as one of the most impactful research papers written by Children’s National authors in 2016.

In the intervening months, a multidisciplinary team at Children National has consulted on 66 pregnancies and infants with confirmed or suspected Zika exposure. Thirty-five of the Zika-related evaluations were prenatal, and 31 postnatal evaluations assessed the impact of in utero Zika exposure after the babies were born.

The continuum of Zika-related injuries includes tragedies, such as a 28-year-old pregnant woman who was referred to Children’s National after imaging hinted at microcephaly. Follow-up with sharper magnetic resonance imaging (MRI) identified severe diffuse thinning of the cerebral cortical mantle, evidence of parenchymal cysts in the white matter and multiple contractures of upper and lower extremities with muscular atrophy.

According to a registry of Zika-affected pregnancies maintained by the CDC, one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection has resulted in birth defects in the fetus or infant.

“More surprising than that percentage is the fact that just 25 percent of infants underwent neuroimaging after birth – despite the CDC’s recommendation that all Zika-exposed infants undergo postnatal imaging,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National. “Clinicians should follow the CDC’s guidance to the letter, asking women about possible exposure to Zika and providing multidisciplinary care to babies after birth. Imaging is an essential tool to accurately monitor the growing baby’s brain development.”

Adré du Plessis, M.B.Ch.B., M.P.H., director of the Fetal Medicine Institute and Congenital Zika Virus Program co-leader, explains the challenges: ”When it comes to understanding the long-term consequences for fetuses exposed to the Zika virus, we are still on the steepest part of the learning curve. Identifying those children at risk for adverse outcomes will require a sustained and concerted multidisciplinary effort from conception well beyond childhood.”

In addition to counseling families in the greater Washington, D.C. region, the Children’s research team is collaborating with international colleagues to conduct a clinical trial that has been recruiting Zika-infected women and their babies in Colombia. Pediatric Resident Youssef A. Kousa, D.O., Ph.D., M.S., and Neurologist Sarah B. Mulkey, M.D., Ph.D., will present preliminary findings during Research and Education Week 2017.

In Colombia as well as the District of Columbia, a growing challenge continues to be assessing Zika’s more subtle effects on pregnancies, developing fetuses and infants, says Radiologist Dorothy Bulas, M.D., another member of Children’s multidisciplinary Congenital Zika Virus Program.

The most severe cases from Brazil were characterized by interrupted fetal brain development, smaller-than-normal infant head circumference, brain calcifications, enlarged ventricles, seizures and limbs folded at odd angles. In the United States and many other Zika-affected regions, Zika-affected cases with such severe birth defects are outnumbered by infants who were exposed to Zika in utero but have imaging that appears normal.

In a darkened room, Dr. Bulas pores over magnified images of the brains of Zika-infected babies, looking for subtle differences in structure that may portend future problems.

“There are some questions we have answered in the past year, but a number of questions remain unanswered,” Dr. Bulas says. “For neonates, that whole area needs assessment. As the fetal brain is developing, the Zika virus seems to affect the progenitor cells. They’re getting hit quite early on. While we may not detect brain damage during the prenatal period, it may appear in postnatal images. And mild side effects that may not be as obvious early on still have the potential to be devastating.”

test tubes

2016: A banner year for innovation

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test tubes

In 2016, clinicians and research scientists working at Children’s National Health System published more than 1,100 articles in high-impact journals about a wide array of topics. A Children’s Research Institute review group selected the top articles for the calendar year considering, among other factors, work published in top-tier journals with impact factors of 9.5 and higher.

“Conducting world-class research and publishing the results in prestigious journals represents the pinnacle of many research scientists’ careers. I am pleased to see Children’s National staff continue this essential tradition,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “While it was difficult for us to winnow the field of worthy contenders to this select group, these papers not only inform the field broadly, they epitomize the multidisciplinary nature of our research,” Dr. Batshaw adds.

The published papers explain research that includes discoveries made at the genetic and cellular levels, clinical insights and a robotic innovation that promises to revolutionize surgery:

  • Outcomes from supervised autonomous procedures are superior to surgery performed by expert surgeons
  • The Zika virus can cause substantial fetal brain abnormalities in utero, without microcephaly or intracranial calcifications
  • Mortality among injured adolescents was lower among patients treated at pediatric trauma centers, compared with adolescents treated at other trauma center types
  • Hydroxycarbamide can substitute for chronic transfusions to maintain transcranial Doppler flow velocities for high-risk children with sickle cell anemia
  • There is convincing evidence of the efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease
  • Sirt1 is an essential regulator of oligodendrocyte progenitor cell proliferation and oligodendrocyte regeneration after neonatal brain injury

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2017 at Children’s National, a weeklong event that begins April 24. This year’s theme, “Collaboration Leads to Innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

fruit fly

Studying fruit flies to better understand human kidneys

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fruit fly

In his latest study, Zhe Han and co-authors zeroed in on Rab genes to determine their role in fruit fly renal function.

It’s a given that fruit flies and humans are different. Beyond the obvious are a litany of less-apparent distinctions. For example, fruit flies have hemolymph instead of blood. Arranged around a single cardiac chamber, compared with humans’ four-chamber hearts, are a group of cells called nephrocytes that serve the same function as human kidneys, filtering toxins and waste from hemolymph.

But despite the dissimilarities between these two organisms, fly nephrocytes and human kidney cells are similar enough to allow the fruit fly, a common lab model that shares about 60 percent of its DNA with people, to provide insights on kidney disease in people. In a new study in fruit flies led by Zhe Han, Ph.D., principal investigator and associate professor in the Center for Cancer and Immunology Research at Children’s National Health System, researchers identified several new genes thought to be critical for renal function in humans. The findings could lend insight to the inner workings of this organ down to the molecular level and eventually help further the understanding or treatment of kidney disorders.

Han explains that recent research by his group tied 80 fruit fly genes to renal function. Many of these newly identified genes were Rab GTPases, a family of genes that make proteins whose job is to move substances around in cells through membrane-enclosed pouches called vesicles. For example, Rab proteins might put some substances on the path to destruction by moving them into lysosomes, vesicles with enzymes that break down all kinds of biomolecules. Rab proteins might help other substances be reused by steering them into recycling endosomes, vesicles that shuttle biomolecules that are still useful to where they will be used next.

In their latest study, published online Feb. 8, 2017 in Cell & Tissue Research, Han and co-authors zeroed in on these Rab genes to determine their role in fruit fly renal function. The researchers accomplished this by using genetic alterations to shut down each gene selectively in fruit fly nephrocytes. They then evaluated these transgenic flies on a number of different characteristics, including ability to effectively filter proteins from the blood, whether toxins placed in their food accumulated in their nephrocytes, how they developed and how they survived.

Their findings readily identified five Rab genes that seemed more important for these functions than the others: Rabs 1, 5, 7, 11 and 35, which all have analogous genes in humans.

Peering into the nephrocytes of flies in which these three Rabs had been silenced, the researchers made critical discoveries. Turning off Rab 7 appeared to block the path toward biomolecules in the cell entering lysosomes. Rather than biomolecules being destroyed, they instead were shuttled to the recycling route. Turning off Rab 11 had the reverse effect; recycling endosomes were drastically reduced, while lysosomes dramatically increased. Turning off Rab 5 had the most striking effect: All vesicles going in or out were blocked – like a cellular traffic jam – filling the cell with biomolecules that had no place to go, Han says.

Han, who has long tracked renal-related mutations in humans, says that no patients with kidney disease have turned up so far with Rab mutations. These genes are critical for functions throughout the body, he explains, so any embryos with these mutations are unlikely to survive. However, he adds, a host of other renal-related genes work in parallel or are controlled by different Rabs. So understanding the role of Rabs in renal function provides some insight into how these genes operate as well as what might happen when the function of these genes goes awry.

Han plans to study how Rabs 5, 7 and 11 fit into networks of renal genes as well as the role of the other Rabs that could play novel roles in the nephrocyte cell trafficking.

“These findings in fly Rabs provide the framework to study the major causes of kidney disease in human patients,” he adds.

Zhe Han

Fruit flies can model human genetic kidney disease

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Zhe Han

Zhe Han, Ph.D., has found that a majority of human genes known to be associated with nephrotic syndrome play conserved roles in renal function, from fruit flies to humans.

Drosophila melanogaster, the common fruit fly, has played a key role in genetic research for decades. Even though D. melanogaster and humans look vastly different, researchers estimate that about 75 percent of human disease-causing genes have a functional homolog in the fly.

A Children’s National Health System research team reported in a recent issue of Human Molecular Genetics that the majority of genes associated with nephrotic syndrome (NS) in humans also play pivotal roles in Drosophila renal function, a conservation of function across species that validates transgenic flies as ideal pre-clinical models to improve understanding of human disease.

NS is a cluster of symptoms that signal kidney damage, including excess protein in urine, low protein levels in blood, elevated cholesterol and swelling. Research teams have identified mutations in more than 40 genes that cause genetic kidney disease, but knowledge gaps remain in understanding the precise roles that specific genes play in kidney cell biology and renal disease. To address those research gaps, Zhe Han, Ph.D., a principal investigator and associate professor in the Center for Cancer & Immunology Research at Children’s National, and colleagues systematically studied NS-associated genes in the Drosophila model, including seven genes whose renal function had never been analyzed in a pre-clinical model.

“Eighty-five percent of these genes are required for nephrocyte function, suggesting that a majority of human genes known to be associated with NS play conserved roles in renal function from flies to humans,” says Han, the paper’s senior author. “To hone in on functional conservation, we focused on Cindr, the fly’s version of the human NS gene, CD2AP,” Han adds. “Silencing Cindr in nephrocytes led to dramatic impairments in nephrocyte function, shortened their life span, collapsed nephrocyte lacunar channels – the fly’s nutrient circulatory system – and effaced nephrocyte slit diaphragms, which diminished filtration function.”

And, to confirm that the phenotypes they were studying truly caused human disease, they reversed the damage by expressing a wild-type human CD2AP gene. A mutant allele derived from a patient with CD2AP-associated NS did not rescue the phenotypes.

Thus, the Drosophila nephrocyte can be used to explain the clinically relevant molecular mechanisms underlying the pathogenesis of most monogenic forms of NS, the research team concludes. “This is a landmark paper for using the fly to study genetic kidney diseases,” Han adds. “For the first time, we realized that the functions of essential kidney genes could be so similar from the flies to humans.”

A logical next step will be to generate personalized in vivo models of genetic renal diseases bearing patient-specific mutations, Han says. These in vivo models can be used for drug screens to identify treatments for kidney diseases that currently lack therapeutic options, such as most of the 40 genes studies in this paper as well as the APOL1 gene that is associated with the higher risk of kidney diseases among millions of African Americans.

Sarah B. Mulkey

Researchers tackle Zika’s unanswered questions

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Youssef A. Kousa

Youssef A. Kousa, D.O., Ph.D., M.S., is examining whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections.

A Maryland woman traveled to the Dominican Republic early in her pregnancy, spending three weeks with family. She felt dizzy and tired and, at first, attributed the lethargy to jet lag. Then, she experienced a rash that lasted about four days. She never saw a bite or slapped a mosquito while in the Dominican Republic but, having heard about the Zika virus, asked to be tested.

Her blood tested positive for Zika.

Why was this pregnant woman infected by Zika while others who live year-round in Zika hot zones remain free of the infectious disease? And why was she among the slim minority of Zika-positive people to show symptoms?

Youssef A. Kousa, D.O., Ph.D., M.S., a pediatric resident in the child neurology track at Children’s National Health System, is working on a research study that will examine whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections during pregnancy, leaving  some fetuses at higher risk of developing microcephaly.

Dr. Kousa will present preliminary findings during Research and Education Week 2017 at Children’s National.

At sites in Puerto Rico, Colombia and Washington D.C., Dr. Kousa and his research collaborators are actively recruiting study participants and drawing blood from women whose Zika infections were confirmed in the first or second trimester of pregnancy. The blood is stored in test tubes with purple caps, a visual cue that the tube contains an additive that binds DNA, preventing it from being cut up. Additional research sites are currently being developed.

When the blood arrives at Children’s National, Dr. Kousa will use a centrifuge located in a sample preparation room to spin the samples at high speed for 11 minutes. The sample emerges from the centrifuge in three discrete layers, separated by weight. The rose-colored section that rises to the top is plasma. Plasma contains tell-tale signs of the immune system’s past battles with viruses and will be analyzed by Roberta L. DeBiasi, M.D., M.S., Chief of the Division of Pediatric Infectious Diseases at Children’s National, and Dr. Kousa’s mentor.

A slender line at the middle indicates white blood cells. The dark red layer is heavier red blood cells that sink to the bottom. This bottom half of the test tube, where the DNA resides, is where Dr. Kousa will perform his genetic research.

For years, Dr. Kousa has worked to identify genetic risk factors that influence which fetuses develop cleft lip and palate. In addition to genetic variances that drive disease, he looks at environmental overlays that can trigger genes to respond in ways that cause pediatric disease. When Zika infections raced across the globe, he says it was important to apply the same genetic analyses to the emerging disease. Genes make proteins that carry out instructions, but viral infection disrupts how genes interact, he says. Cells die. Other cells do not fully mature.

While certain poverty-stricken regions of Brazil have recorded the highest spikes in rates of microcephaly, more is at play than socioeconomics, he says. “It didn’t feel like all of the answers lie in the neighborhood. One woman with a Zika-affected child can live just down the street from a child who is more or less severely affected by Zika.”

As a father, Dr. Kousa is particularly concerned about how Zika stunts growth of the fetal brain at a time when it should expand exponentially. “I have three kids. You see them as they achieve milestones over time. It makes you happy and proud as a parent,” he says.

Sarah B. Mulkey

Sarah B. Mulkey, M.D., Ph.D., is studying whether infants exposed to Zika in utero achieve the same developmental milestones as uninfected infants.

While Dr. Kousa concentrates on Zika’s most devastating side effects, his colleague Sarah B. Mulkey, M.D., Ph.D., is exploring more subtle damage Zika can cause to fetuses exposed in utero. In the cohort of Colombian patients that Dr. Mulkey is researching, just 8 percent had abnormal fetal brain magnetic resonance images (MRIs). At first glance, the uncomplicated MRIs appear to be reassuring news for the vast majority of pregnant women.

Dr. Mulkey also will present preliminary findings during Research and Education Week 2017 at Children’s National.

In the fetus, the Zika virus makes a beeline to the developing brain where it replicates with ease and can linger after birth. “We need to be cautious about saying the fetal MRI is ‘normal’ and the infant is going to be ‘normal,’ ” Dr. Mulkey says. “We know with congenital cytomegalovirus that infected infants may not show symptoms at birth yet suffer long-term consequences, such as hearing deficits and vision loss.”

Among Zika-affected pregnancies in Colombia in which late-gestational age fetal MRIs were normal, Dr. Mulkey will use two different evaluation tools at 6 months and 1 year of age to gauge whether the babies accomplish the same milestones as peers. One evaluation tool is a questionnaire that has been validated in Spanish.

At 6 months and 1 year of age, the infants’ motor skills will be assessed, such as their ability to roll over in both directions, sit up, draw their feet toward their waist, stand, take steps independently and purposefully move their hands. Videotapes of the infants performing the motor skills will be scored by Dr. Mulkey and her mentor, Adre du Plessis, M.B.Ch.B., Chief of the Division of Fetal and Transitional Medicine at Children’s National. The Thrasher Research Fund is funding the project, “Neurologic outcomes of apparently normal newborns from Zika virus-positive pregnancies,” as part of its Early Career Award Program.

Both research projects are extensions of a larger multinational study co-led by Drs. du Plessis and DeBiasi that explores the impact of prolonged Zika viremia in pregnant women, fetuses and infants; the feasibility of using fetal MRI to describe the continuum of neurological impacts in Zika-affected pregnancies; and long-term developmental issues experienced by Zika-affected infants.

FSH Society awards grant to Yi-Wen Chen

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The FSH Society has awarded the FSH Society Grant FSHS-82016-4 to Children’s National researcher Yi-Wen Chen, D.M.V., Ph.D., to study facioscapulohumeral muscular dystrophy (FSHD).

Chen, Principal Investigator at the Center for Genetic Medicine Research at Children’s National and associate professor of pediatrics and integrative systems biology at George Washington University, will receive the research grant of $179,104 for two years for her project titled “Developing LNA-based therapy for facioscapulohumeral muscular dystrophy.”

FSHD is a complex genetic disorder caused by aberrantly expressed double homeobox protein 4 (DUX4) in patients’ cells that ultimately leads to the weakening of skeletal muscles often beginning in teenage years or early adulthood. Her research will focus on the next phases of developing LNA-based therapy for patients with FSHD through an in vivo study in a preclinical model.

“We have been designing compounds to inject into a preclinical model of FSHD in order to first reduce the DUX4 in the muscle and then identify the compounds that work best,” says Chen. Researchers will inject varying doses of the compound directly into the muscle for localized delivery and under the skin to reach the entire body for systemic delivery.

Currently there is no treatment for FSHD. After 15 years spent researching the disease, Chen hopes to test the efficacy of the compounds in order to identify a treatment.

Teen Girl drawing a heart on an iPad

Illuminating cardiometabolic risk in Down syndrome

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Teen Girl drawing a heart on an iPad

A leading researcher at Children’s National says researchers should look closely at the increased risks of obesity and thyroid disease common in patients with Down Syndrome, and determine how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

Over the last several decades, physicians’ improved ability to treat the common comorbidities of Down syndrome, such as congenital heart disease, has dramatically prolonged survival. Today, more than 400,000 people across the country are living with Down syndrome, and life expectancy has increased to 60 years.

New strategies to manage care for patients with Down syndrome must include preventive, evidence-based approaches to address the unique needs of these patients, according to Sheela N. Magge, M.D., M.S.C.E., Director of Research in the Division of Endocrinology and Diabetes at Children’s. She says that these efforts should include looking more closely at the increased risks of obesity and thyroid disease common in this population, and determining how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

An NIH-funded study from Children’s National and the Children’s Hospital of Philadelphia (CHOP), led by Dr. Magge and her colleague from CHOP, Dr. Andrea Kelly, seeks to better understand how the body composition of patients with Down syndrome impacts their likelihood for developing diabetes and obesity-related cardiovascular risks long term.

“We know that individuals with Down syndrome are at increased risk for obesity, but what hasn’t been clear is whether or not they also have the same cardiometabolic risk associated with obesity that we know holds true for other populations,” says Dr. Magge. “In this previously under-studied population, the common assumption based on very limited studies from the 1970’s was that individuals with Down syndrome were protected from the diabetes and cardiovascular risks that can develop in other overweight people. However, more recent epidemiologic studies contradict those early findings.”

The study has enrolled 150 Down syndrome patients and almost 100 controls to date, and the team is currently beginning to analyze the data. Dr. Magge believes that the findings from this study will help to provide new, research-driven evidence to inform the long term clinical management of obesity and cardiometabolic risk in adolescents with Down syndrome.

She concludes, “The goal is for our research to provide the foundation that will advance prevention and treatment strategies for this understudied group, so that individuals with Down syndrome not only have a longer life expectancy, but also a healthier and better quality of life.”

cord blood

T-cell therapy success for relapsing blood cancer

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cord blood

A unique immunotherapeutic approach that expands the pool of donor-derived lymphocytes (T-cells) that react and target three key tumor-associated antigens (TAA) is demonstrating success at reducing or eliminating acute leukemias and lymphomas when these cancers have relapsed following hematopoietic stem cell transplant (HSCT).

“There’s currently a less than 10 percent chance of survival for a child who relapses leukemia or lymphoma after a bone marrow transplant—in part because these patients are in a fragile medical condition and can’t tolerate additional intense therapy,” says Kirsten Williams, M.D., a blood and marrow transplant specialist in the Division of Hematology at Children’s National Health System, and principal investigator of the Research of Expanded multi-antigen Specifically Oriented Lymphocytes for the treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE) clinical trial.

The unique manufactured donor-derived lymphocytes used in this multi-institutional Phase 1 dose-ranging study are receptive to multiple tumor-associated antigens within the cell, including WT1, PRAME, and Survivin, which have been found to be over-expressed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), B-cell AML/MDS, B-cell acute lymphoblastic leukemia (ALL), and Hodgkins lymphoma. Modifying the lymphocytes for several antigens, rather than a single target, broadens the ability of the T-cells to accurately target and eradicate cancerous cells.

Preliminary results demonstrate a 78 percent response rate to treatment, and a 44 percent rate of total remission for participating patients. To date, nine evaluable patients with refractory and relapsed AML/MDS, B-cell ALL, or Hodgkins lymphoma have received 1-3 infusions of the expanded T-cells, and of those, seven have responded to the treatment, showing reduction in cancer cells after infusion with little or no toxicity. All of these patients had relapse of their cancer after hematopoietic cell transplantation. The study continues to recruit eligible patients, with the goal of publishing the full study results within the next 12 months.

“Our preliminary data also shows that this new approach has few if any side effects for the patient, in part because the infused T-cells target antigens that are found only in cancer cells and not found in healthy tissues,” Dr. Williams notes.

The approach used to expand existing donor-derived TAA-lymphocytes, rather than using unselected T cells or genetically modified T-cells as in other trials, also seems to reduce the incidence of post infusion graft versus host disease and other severe inflammatory side effects. Those side effects typically occur when the infused lymphocytes recognize healthy tissues as foreign and reject them or when the immune system reacts to the modified elements of the lymphocytes, she adds.

“These results are exciting because they may present a truly viable option for the 30 to 40 percent of children who will relapse post-transplant,” Dr. Williams concludes. “Many of the patients who participated were given two options: palliative care or this trial. To see significant success and fewer side effects gives us, and families with children facing relapsing leukemia, some hope for this new treatment.”

Dr. Williams discussed the early outcomes of the RESOLVE trial during an oral presentation at the American Society for Blood and Marrow Transplantation meeting on February 22, 2017.

“The early indicators are very promising for this patient population,” says Catherine Bollard, M.D., M.B.Ch.B., Chief of the Division of Allergy and Immunology, Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, and senior author of the study. “If we can achieve this, and continue to see good responses with few side effects, it’s possible these methods could become a viable alternative to HSCT for patients with no donor match or who aren’t likely to tolerate transplant.”

This is one of the first immunotherapeutic approaches to successfully capitalize on the natural ability of human T-cells to kill cancer, though previous research has shown significant success for this approach in reducing the deadly impact of several viruses, including Epstein-Barr virus, adenovirus, and cytomegalovirus, post HSCT. These new findings have led to the development of additional clinical trials to investigate applications of this method of TAA-lymphocyte manufacture and infusion for pre-HSCT MDS/AML, B-cell ALL, Hodgkins Lymphoma, and even some solid tumors.

Sarah B. Mulkey

Puzzling symptoms lead to collaboration

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Sarah B. Mulkey, explaining the research

Sarah B. Mulkey, M.D., Ph.D., is lead author of a study that describes a brand-new syndrome that stems from mutations to KCNQ2, a genetic discovery that began with one patient’s unusual symptoms.

Unraveling one of the greatest mysteries of Sarah B. Mulkey’s research career started with a single child.

At the time, Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National Health System, was working at the University of Arkansas for Medical Sciences. Rounding one morning at the neonatal intensive care unit (NICU), she met a new patient: A newborn girl with an unusual set of symptoms. The baby was difficult to wake and rarely opened her eyes. Results from her electroencephalogram (EEG), a test of brain waves, showed a pattern typical of a severe brain disorder. She had an extreme startle response, jumping and twitching any time she was disturbed or touched, that was not related to seizures. She also had trouble breathing and required respiratory support.

Dr. Mulkey did not know what to make of her new patient: She was unlike any baby she had ever cared for before. “She didn’t fit anything I knew,” Dr. Mulkey remembers, “so I had to get to the bottom of what made this one child so different.”

Suspecting that her young patient’s symptoms stemmed from a genetic abnormality, Dr. Mulkey ran a targeted gene panel, a blood test that looks for known genetic mutations that might cause seizures or abnormal movements. The test had a hit: One of the baby’s genes, called KCNQ2, had a glitch. But the finding deepened the mystery even further. Other babies with a mutation in this specific gene have a distinctly different set of symptoms, including characteristic seizures that many patients eventually outgrow.

Dr. Mulkey knew that she needed to dig deeper, but she also knew that she could not do it alone. So, she reached out first to Boston Children’s Hospital Neurologist Philip Pearl, M.D., an expert on rare neurometabolic diseases, who in turn put her in touch with Maria Roberto Cilio, M.D., Ph.D., of the University of California, San Francisco and Edward Cooper, M.D., Ph.D., of Baylor College of Medicine. Drs. Cilio, Cooper and Pearl study KCNQ2 gene variants, which are responsible for causing seizures in newborns.

Typically, mutations in this gene cause a “loss of function,” causing the potassium channel to remain too closed to do its essential job properly. But the exact mutation that affected KCNQ2 in Dr. Mulkey’s patient was distinct from others reported in the literature. It must be doing something different, the doctors reasoned.

Indeed, a research colleague of Drs. Cooper, Cilio and Pearl in Italy — Maurizio Taglialatela, M.D., Ph.D., of the University of Naples Federico II and the University of Molise — had recently discovered in cell-based work that this particular mutation appeared to cause a “gain of function,” leaving the potassium channel in the brain too open.

Wondering whether other patients with this same type of mutation had the same unusual constellation of symptoms as hers, Dr. Mulkey and colleagues took advantage of a database that Dr. Cooper had started years earlier in which doctors who cared for patients with KCNQ2 mutations could record information about symptoms, lab tests and other clinical findings. They selected only those patients with the rare genetic mutation shared by her patient and a second rare KCNQ2 mutation also found to cause gain of function — a total of 10 patients out of the hundreds entered into the database. The researchers began contacting the doctors who had cared for these patients and, in some cases, the patients’ parents. They were scattered across the world, including Europe, Australia and the Middle East.

Dr. Mulkey and colleagues sent the doctors and families surveys, asking whether these patients had similar symptoms to her patient when they were newborns: What were their EEG results? How was their respiratory function? Did they have the same unusual startle response?

She is lead author of the study, published online Jan. 31, 2017 in Epilepsia, that revealed a brand-new syndrome that stems from specific mutations to KCNQ2. Unlike the vast majority of others with mutations in this gene, Dr. Mulkey and her international collaborators say, these gain-of-function mutations cause a distinctly different set of problems for patients.

Dr. Mulkey notes that with a growing focus on precision medicine, scientists and doctors are becoming increasingly aware that knowing about the specific mutation matters as much as identifying the defective gene. With the ability to test for more and more mutations, she says, researchers likely will discover more cases like this one: Symptoms that differ from those that usually strike when a gene is mutated because the particular mutation differs from the norm.

Such cases offer important opportunities for researchers to come together to share their collective expertise, she adds. “With such a rare diagnosis,” Dr. Mulkey says, “it’s important for physicians to reach out to others with knowledge in these areas around the world. We can learn much more collectively than by ourselves.”

Lisa M. Guay-Woodford, M.D

Lisa Guay-Woodford: minimizing kidney disease effects

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Lisa M. Guay-Woodford, M.D

Lisa M. Guay-Woodford, M.D., is internationally recognized for her examination of the mechanisms that make certain inherited renal disorders particularly lethal, a research focus inspired by her patients.

The artist chose tempera paint for her oeuvre. The flower’s petals are the color of Snow White’s buddy, the Bluebird of Happiness. Each petal is accentuated in stop light red, and the blossom’s leaves stretch up toward the sun. With its bold strokes and exuberant colors, the painting exudes life itself.

It’s the first thing Lisa M. Guay-Woodford, M.D., sees when she enters her office. It’s the last thing she sees as she leaves.

Dr. Guay-Woodford, a pediatric nephrologist, is internationally recognized for her research into the mechanisms that make certain inherited renal disorders, such as autosomal recessive polycystic kidney disease (ARPKD), particularly lethal. She also studies disparate health disorders that have a common link: Disruption to the cilia, slim hair-like structures that protrude from almost every cell in the human body and that play pivotal roles in human genetic disease.

Sarah, the artist who painted the bright blue flower more than 20 years ago when she was 8, was one of Dr. Guay-Woodford’s patients. And she’s part of the reason why Dr. Guay-Woodford has spent much of her career focused on the broader domain of disorders tied to just a single defective gene, such as ARPKD.

“It dates back to when I was a house officer and took care of kids with this disorder,” Dr. Guay-Woodford says. “Maybe 30 percent die in the newborn period. Others survive, but they have a whole range of complications.”

Two of her favorite patients died from ARPKD-related reasons in the same year. One died from uncontrolled high blood pressure. The other, Sarah, died from complications from a combined kidney and liver transplant.

“The picture she drew hangs in my office,” she says. “She was a wonderful kid who was really full of life, and what she chose really mirrored who she was as a person. We put up lots of those sorts of those things in my office. It’s a daily reminder of why we do the things we do and the end goal.”

ARPKD is characterized by the growth of cysts in the liver, the kidney – which can lead to kidney failure – and complications within other structures, such as blood vessels in the heart and brain, according to the National Institutes of Health. About 1 in 20,000 live births is complicated by the genetic disorder. The age at which symptoms arise varies.

“Given the way it plays out, starting in utero, this is not a disease we are likely to cure,” she says. “But there are children who have very minimal complications. The near-term goal is to use targeted therapies to convert the children destined to have a more severe disease course to one that is less complicated so that no child suffers the full effects of the disease.”

That’s why it is essential to attain detailed knowledge about the defective gene responsible for ARPKD. To that end, Dr. Guay-Woodford participated in an international collaboration – one of three separate groups that 14 years ago identified PKHD1 as the defective gene that underlies ARPKD.

“The progress has been slow, partly because the gene and its protein products are very complex,” she says. “The good news is the gene has been identified. The daunting news is the identification did not leap us forward. It is just sort of an important step in what is going to be a fits-and-starts kind of journey.”

The field is trying to emulate the clinical successes that have occurred for patients with cystic fibrosis, which now can be treated by a drug that targets the defective gene, attacking disease at a fundamental level. Patient outcomes also have improved due to codifying care.

When she was a resident in the 1980s, children with cystic fibrosis died in their teens. “Now, they’re living well into their 40s because of careful efforts by really astute clinicians to deliver a standardized approach to care, an approach now enhanced by a terrific new drug. We measure quality care in terms of patient outcomes. That has allowed us to really understand how to effectively use antibiotics, physical therapy and how to think about nutrition – which makes a hugely important contribution that previously had been underappreciated.”

Standardizing clinical approaches dramatically improved and extended patients’ lives. “For renal cystic disease, we are beginning to do that better and better,” she adds.

There’s no targeted medicine yet for ARPKD. But thanks to an international conference that Dr. Guay-Woodford convened in Washington in 2013, such consensus expert recommendations have been published to guide diagnosis, surveillance and management of pediatric patients with ARPKD.

“There is an awful lot we can do in the way we systematically look at the clinical disease in these patients and improve our management. And, if you can overlay on top of that specific insights about why one person goes one way in disease progression versus another way, I think we can boost the baseline by developing good standards of care,” she says.

“Science does march on. There are a number of related research studies that are expanding our understanding of ARPKD. Within the next decade, we probably will be able to capitalize on not just the work in ARPKD but work in related diseases to learn the entry points for targeting therapies. That way, we can build a portfolio of markers of disease progression and test how effective these potential therapies are in slowing the course of the disease.”

Muscular Dystrophy Association awards grants to two Children’s National scientists

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Marshall Hogarth, Ph.D

Marshall Hogarth, Ph.D

James Novak, Ph.D.

James Novak, Ph.D.

Two Children’s National Health System research scientists, Marshall Hogarth, Ph.D. and James Novak, Ph.D., have received Post-Doctoral Development Grants from the Muscular Dystrophy Association (MDA) as part of funding awarded to young, rising researchers who are poised to become independent investigators.

Over the next three years, Hogarth and Novak will be allotted $180,000 each to underwrite their individual research projects.

Hogarth’s research is focused on limb-girdle muscular dystrophy (LGMD), a disease which presents as muscle weakness when patients are in their late teens before rapidly progressing to severe debilitation. The MDA grant will allow Hogarth to continue his research investigating the replacement of muscle with fatty tissue and the role this plays in the late onset and subsequent progression of LGMD in patients.

Novak focuses mainly on researching Duchenne Muscular Dystrophy (DMD), a severely debilitating form of MD, that leads to progressive muscle weakness and respiratory and cardiac failure. Currently, the only Food and  Drug Administration (FDA)  approved treatment for DMD is exon-skipping. The MDA grant will support Novak’s study of the mechanisms that regulate the delivery of exon-skipping drugs in muscle, in order to identify new therapeutic targets and improve drug efficacy for patients with DMD.

While Hogarth and Novak focus on different aspects of neuromuscular disease, both look forward to making significant contributions that lead to overall improvements in the treatment of patients impacted by muscular dystrophy.

Eric Vilain, M.D., Ph.D.

Eric Vilain to lead genetic medicine research

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Eric Vilain

Eric Vilain, M.D., Ph.D., emphasizes the idea of health and disease as a compound process that will transform children’s health and impact a patient throughout life.

Eric Vilain, M.D., Ph.D., an internationally renowned geneticist well known for groundbreaking studies of gender based biology, will soon lead the Center for Genetic Medicine Research at Children’s National Health System.

Dr. Vilain joins Children’s National from the University of California, Los Angeles (UCLA) where he serves as Professor of Human Genetics, Pediatrics and Urology, Chief of Medical Genetics, and attending physician in the Department of Pediatrics.

As the Director of the Center for Genetic Medicine Research, Dr. Vilain will emphasize the idea of health and disease as a compound process, which he believes “can transform children’s health and help the treatment and prevention of illness, not only in childhood, but throughout a patient’s life.”

The Center for Genetic Medicine Research currently houses a highly interdisciplinary faculty of over 50 scientists and physician investigators and brings together a variety of clinical and scientific disciplines to coordinate scientific and clinical investigations simultaneously from multiple angles. The Center also provides access to the leading edge innovative technologies in genomics, microscopy, proteomics, bioinformatics, pre-clinical drug trials, and multi-site clinical trial networks for faculty within the Children’s Research Institute, the academic arm of Children’s National.

Dr. Vilain’s current laboratory focuses on the genetics of sexual development and sex differences – specifically the molecular mechanisms of gonad development and the genetic variants of brain sexual differentiation. His research also explores the biological bases of sex variations in predisposition to disease. His work crosses several disciplines (genetics, neuroscience, psychology) leading to findings with major societal implications. In addition to scientific investigation, Dr. Vilain created a clinic devoted to caring for patients with a wide array of genetic and endocrine issues, particularly those with variations of sexual development.

He brings nearly 30 years of expertise with him to Children’s National. He has authored seminal articles regarding the field of sexual development, and his research program has continuously been funded by the National Institutes of Health (NIH). Dr. Vilain is a Fellow of the American College of Medical Genetics and a member of numerous professional committees. The recipient of numerous awards, he has been recognized by organizations ranging from the NIH to the Doris Duke Charitable Foundation, March of Dimes, and the Society for Pediatric Research. He has served as an advisor to the International Olympic Committee Medical Commission since 2011 and has been a member of the Board of Scientific Counselors of the National Institute of Child Health and Human Development since 2015.

Mark Batshaw, M.D., Executive Vice President, Physician-in-Chief, and Chief Academic Officer at Children’s National says, “Dr. Vilain’s vision and expertise in the study and use of precision medicine approaches, and the development of novel treatments for diseases of childhood, will lead to drastically different and improved outcomes for some of the most devastating diseases, such as cancer.”

“I am honored to join the world-renowned team at Children’s National, and look forward to continuing to find new, innovative ways to research, diagnose and treat rare and common disorders,” Dr. Vilain adds.

Doctor holding preemie's hand

Children’s National creates first-of-its-kind Rare Disease Institute

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Children’s National Health System has announced the creation of the Children’s National Rare Disease Institute (CNRDI), a first-of-its-kind clinical research center focused exclusively on the care and treatment of children and adults with rare genetic disorders. Designated by the National Organization for Rare Disorders (NORD) as the first Center of Excellence for Clinical Care for Rare Diseases, the CNRDI will focus on developing care standards for patients, advancing research and developing new therapies to better treat rare diseases. The institute will be led by Marshall Summar, M.D., Chief of Genetics and Metabolism at Children’s National, and will collaborate with the NORD natural history/registry program, which was developed with input from the U.S. Food and Drug Administration and the National Institutes of Health to advance monitoring databases for patient outcomes and disease.

Vittorio Gallo

Vittorio Gallo named Chief Research Officer

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Vittorio Gallo

As chief research officer, Vittorio Gallo, Ph.D., will be instrumental in developing and realizing Children’s Research Institute’s long-term strategic vision.

Children’s National Health System has appointed the longtime director of its Center for Neuroscience Research, Vittorio Gallo, Ph.D., as Chief Research Officer. Gallo’s appointment comes at a pivotal time for the institution’s research strategic plan, as significant growth and expansion will occur in the next few years. Gallo is a neuroscientist who studies white matter disorders, with particular focus on white matter growth and repair. He is also the Wolf-Pack Chair in Neuroscience at Children’s Research Institute, the academic arm of Children’s National.

As Chief Research Officer, Gallo will be instrumental in developing and realizing Children’s Research Institute’s long-term strategic vision, which includes building out the nearly 12-acre property once occupied by Walter Reed National Military Medical Center to serve as a regional innovation hub and to support Children’s scientists conducting world-class pediatric research in neuroscience, genetics, clinical and translational science, cancer and immunology. He succeeds Mendel Tuchman, M.D., who has had a long and distinguished career as Children’s Chief Research Officer for the past 12 years and who will remain for one year in an emeritus role, continuing federally funded research projects and mentoring junior researchers.

“I am tremendously pleased that Vittorio has agreed to become Chief Research Officer as of July 1, 2017, at such a pivotal time in Children’s history,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “Since Mendel announced plans to retire last summer, I spent a great deal of time talking to Children’s Research Institute investigators and leaders and also asking colleagues around the nation about the type of person and unique skill sets needed to serve as Mendel’s successor. With each conversation, it became increasingly clear that the most outstanding candidate for the Chief Research Officer position already works within Children’s walls,” Dr. Batshaw adds.

“I am deeply honored by being selected as Children’s next Chief Research Officer and am excited about being able to play a leadership role in defining the major areas of research that will be based at the Walter Reed space. The project represents an incredible opportunity to maintain the core nucleus of our research strengths – genetics, immunology, neurodevelopmental disorders and disabilities – and to expand into new, exciting areas of research. What’s more, we have an unprecedented opportunity to form new partnerships with peers in academia and private industry, and forge new community partnerships,” Gallo says. “I am already referring to this as Walter Reed ‘Now,’ so that we are not waiting for construction to begin to establish these important partnerships.”

Gallo’s research focus has been on white matter development and injury, myelin and glial cells – which are involved in the brain’s response to injury. His past and current focus is also on neural stem cells. His work in developmental neuroscience has been seminal in deepening understanding of cerebral palsy and multiple sclerosis. He came to Children’s National from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) intramural program. His intimate knowledge of the workings of the National Institutes of Health (NIH) has helped him to establish meaningful collaborations between both institutions. During his tenure, he has transformed the Center for Neuroscience Research into one of the nation’s premier programs. The Center is home to the prestigious NIH/NICHD-funded District of Columbia Intellectual and Developmental Disabilities Research Center, which Gallo directs.

Children’s research scientists working under the auspices of Children’s Research Institute conduct and promote highly collaborative and multidisciplinary research within the hospital that aims to better understand, treat and, ultimately, prevent pediatric disease. As Chief Research Officer, Gallo will continue to establish and enhance collaborations between research and clinical programs. Such cross-cutting projects will be essential in defining new mechanisms that underlie pediatric disease. “We know, for instance, that various mechanisms contribute to many genetic and neurological pediatric diseases, and that co-morbidities add another layer of complexity. Tapping expertise across disciplines has the potential to unravel current mysteries, as well as to better characterize unknown and rare diseases,” he says.

“Children’s National is among the nation’s top seven pediatric hospitals in NIH research funding, and the extraordinary innovations that have been produced by our clinicians and scientists have been put into practice here and in hospitals around the world,” Dr. Batshaw adds. “Children’s leadership aspires to nudge the organization higher, to rank among the nation’s top five pediatric hospitals in NIH research funding.”

Gallo says the opportunity for Children’s research to expand beyond the existing buildings and the concurrent expansion into new areas of research will trigger more hiring. “We plan to grow our research enterprise through strategic hires and by attracting even more visiting investigators from around the world. By expanding our community of investigators, we aim to strengthen our status as one of the nation’s leading pediatric hospitals,” he says.