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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.

schistosome blood fluke

Therapy derived from parasitic worms downregulates proinflammatory pathways

schistosome blood fluke

A therapy derived from the eggs of the parasitic Schistosoma helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways, reducing inflammation.

A therapy derived from the eggs of parasitic worms helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways and reducing inflammation, indicates the first transcriptome-wide profiling of the bladder during ifosfamide-induced hemorrhagic cystitis.

The experimental model study findings were published online Feb. 7, 2019, in Scientific Reports.

With hemorrhagic cystitis, a condition that can be triggered by anti-cancer therapies like the chemotherapy drug ifosfamide and other oxazaphosphorines, the lining of the bladder becomes inflamed and begins to bleed. Existing treatments on the market carry their own side effects, and the leading therapy does not treat established hemorrhagic cystitis.

Around the world, people can become exposed to parasitic Schistosoma eggs through contaminated freshwater. Once inside the body, the parasitic worms mate and produce eggs; these eggs are the trigger for symptoms like inflammation. To keep their human hosts alive, the parasitic worms tamp down excess inflammation by secreting a binding protein with anti-inflammatory properties.

With that biological knowledge in mind, a research team led by Michael H. Hsieh, M.D., Ph.D., tested a single dose of IPSE, an Interleukin-4 inducing, Schistosoma parasite-derived anti-inflammatory molecule and found that it reduced inflammation, bleeding and urothelial sloughing that occurs with ifosfamide-related hemorrhagic cystitis.

In this follow-up project, experimental models were treated with ifosfamide to learn more about IPSE’s protective powers.

The preclinical models were given either saline or IPSE before the ifosfamide challenge. The bladders of the experimental models treated with ifosfamide had classic symptoms, including marked swelling (edema), dysregulated contraction, bleeding and urothelial sloughing. In contrast, experimental models “pre-treated” with IPSE were shielded from urothelial sloughing and inflammation, the study team found.

Transcriptional profiling of the experimental models’ bladders found the IL-1-B TNFa-IL-6 proinflammatory cascade via NFkB and STAT3 pathways serving as the key driver of inflammation. Pretreatment with IPSE slashed the overexpression of Il-1b, Tnfa and Il6 by 50 percent. IPSE drove significant downregulation of major proinflammatory pathways, including the IL-1-B TNFa-IL-6 pathways, interferon signaling and reduced (but did not eliminate) oxidative stress.

“Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE,” says Dr. Hsieh, a urologist at Children’s National Health System and the study’s senior author. “These preliminary findings reveal several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis in humans.”

When certain chemotherapy drugs are metabolized by the body, the toxin acrolein is produced and builds up in urine. 2-mercaptoethane sulfonate Na (MESNA) binds to acrolein to prevent urotoxicity. By contrast, IPSE targets inflammation at the source, reversing inflammatory changes that damage the bladder.

“Our work demonstrates that there may be therapeutic potential for naturally occurring anti-inflammatory molecules, including pathogen-derived factors, as alternative or complementary therapies for ifosfamide-induced hemorrhagic cystitis,” Dr. Hsieh adds.

In addition to Dr. Hsieh, study co-authors include Lead Author Evaristus C. Mbanefo and Rebecca Zee, Children’s National; Loc Le, Nirad Banskota and Kenji Ishida, Biomedical Research Institute; Luke F. Pennington and Theodore S. Jardetzky, Stanford University; Justin I. Odegaard, Guardant Health; Abdulaziz Alouffi, King Abdulaziz City for Science & Technology; and Franco H. Falcone, University of Nottingham.

Financial support for the research described in this report was provided by the Margaret A. Stirewalt Endowment, the National Institute of Diabetes and Digestive and Kidney Diseases under award R01DK113504, the National Institute of Allergy and Infectious Diseases under award R56AI119168 and a Urology Care Foundation Research Scholar Award.

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.

Preemie Baby

Getting micro-preemie growth trends on track

Preemie Baby

According to Children’s research presented during the Institute for Healthcare Improvement 2018 Scientific Symposium, standardizing feeding practices – including the timing for fortifying breast milk and formula with essential elements like zinc and protein – improves growth trends for the tiniest preterm infants.

About 1 in 10 infants is born before 37 weeks gestation. These premature babies have a variety of increased health risks, including deadly infections and poor lung function.

Emerging research suggests that getting their length and weight back on track could help. According to Children’s research presented during the Institute for Healthcare Improvement 2018 Scientific Symposium, standardizing feeding practices – including the timing for fortifying breast milk and formula with essential elements like zinc and protein – improves growth trends for the tiniest preterm infants.

The quality-improvement project at Children’s National Health System targeted very low birth weight infants, who weigh less than 3.3 pounds (1,500 grams) at birth. These fragile infants are born well before their internal organs, lungs, brain or their digestive systems have fully developed and are at high risk for ongoing nutritional challenges, health conditions like necrotizing enterocolitis (NEC) and overall poor development.

The research team measured progress by tracking the micro-preemies’ mean delta weight Z-score for weight gain, which measures nutritional status.

“In this cohort, mean delta weight Z-scores improved by 43 percent, rising from -1.8 to the goal of -1.0, when we employed an array of interventions. We saw the greatest improvement, 64 percent, among preterm infants who had been born between 26 to 28 weeks gestation,” says Michelande Ridoré, MS, Children’s NICU quality-improvement program lead who presented the group’s preliminary findings. “It’s very encouraging to see improved growth trends just six months after introducing these targeted interventions and to maintain these improvements for 16 months.”

Within Children’s neonatal intensive care unit (NICU), micro-preemies live in an environment that mimics the womb, with dimmed lighting and warmed incubators covered by blankets to muffle extraneous noise. The multidisciplinary team relied on a number of interventions to improve micro-preemies’ long-term nutritional outcomes, including:

  • Reducing variations in how individual NICU health care providers approach feeding practices
  • Fortifying breast milk (and formula when breast milk was not available), which helps these extra lean newborns add muscle and strengthen bones
  • Early initiation of nutrition that passes through the intestine (enteral feeds)
  • Re-educating all members of the infants’ care teams about the importance of standardized feeding and
  • Providing a decision aid about feeding intolerance.

Dietitians were included in the daily rounds, during which the multidisciplinary team discusses each infant’s care plan at their room, and used traffic light colors to describe how micro-preemies were progressing with their nutritional goals. It’s common for these newborns to lose weight in the first few days of life.

  • Infants in the “green” zone had regained their birth weight by day 14 of life and possible interventions included adjusting how many calories and protein they consumed daily to reflect their new weight.
  • Infants in the “yellow” zone between day 15 to 18 of life remained lighter than what they weighed at birth and were trending toward lower delta Z-scores. In addition to assessing the infant’s risk factors, the team could increase calories consumed per day and add fortification, among other possible interventions.
  • Infants in the “red” zone remained below their birth weight after day 19 of life and recorded depressed delta Z-scores. These infants saw the most intensive interventions, which could include conversations with the neonatologist and R.N. to discuss strategies to reverse the infant’s failure to grow.

Future research will explore how the nutritional interventions impact newborns with NEC, a condition characterized by death of tissue in the intestine. These infants face significant challenges gaining length and weight.

Institute for Healthcare Improvement 2018 Scientific Symposium presentation

  • “Improved growth of very low birthweight infants in the neonatal intensive care unit.”

Caitlin Forsythe, MS, BSN, RNC-NIC, NICU clinical program coordinator, Neonatology, and lead author; Michelande Ridoré, MS, NICU quality-improvement program lead; Victoria Catalano Snelgrove, RDN, LD, CNSC, CLC, pediatric clinical dietitian; Rebecca Vander Veer, RD, LD, CNSC, CLC, pediatric clinical dietitian; Erin Fauer, RDN, LD, CNSC, CLC, pediatric clinical dietitian; Judith Campbell, RNC, IBCLC, NICU lactation consultant; Eresha Bluth, MHA, project administrator; Anna Penn, M.D., Ph.D., neonatologist; Lamia Soghier, M.D., MEd, Medical Unit Director, Neonatal Intensive Care Unit; and Mary Revenis, M.D., NICU medical lead on nutrition and senior author; all of Children’s National Health System.

Kwitkin-family-photo

A rare diet: Could you survive on six grams of protein a day?

Clara Barton

Clara Rose Kwitkin was born at a healthy 7 pounds, 14 ounces on Nov. 12, 2018.

Children’s National Health System introduces clinic to help adults with phenylketonuria, a rare inherited disorder, experiment with Palynziq, an FDA-approved drug that helps the body process phenylalanine.

“What can you eat?” is a common question for picky eaters, particularly individuals with phenylketonuria (PKU), a rare inherited metabolic condition that prevents an enzyme in the body from processing the amino acid phenylalanine (Phe), a building block of protein.

About one in 10,000 or 15,000 people in the U.S. with PKU, approximately 50,000 people worldwide, understand this line of questioning. 

“It’s emotional,” says 27-year-old Ashley Kwitkin, a Northern Va. resident and new mom, about the complexities of following a low-Phe diet.

When Kwitkin previously went “off diet,” meaning eating more than six grams of protein a day, the equivalent of a handful of almonds, she felt the consequences: irritability, moodiness and poor concentration. Her body couldn’t process Phe.

The National Institutes of Health mentions excessive levels of Phe can lead to toxic levels in the blood and tissues, and even cause brain damage.

Kwitkin’s motivation during pregnancy quickly changed. “It’s not just me anymore,” notes Kwitkin, who gave birth to Clara Rose Kwitkin on Nov. 12. “It’s me and my child. The moment we met her, our lives changed forever.”  

If Kwitkin went off her PKU-approved diet while pregnant, she may have increased the chance that her baby would have been born with intellectual disabilities, heart problems, delayed growth, microcephaly or behavioral problems.

Fortunately, Kwitkin received medical clearance from her doctors to move forward with a safe and healthy pregnancy. While she is a carrier for PKU, her husband is not – which meant their child had less than a 1 percent change of being born with this rare disease.

Like many adults with PKU, Kwitkin is grateful for advancements with early disease detection and treatment. If she had been born six decades earlier, she may have been hospitalized for neurological impairments, before PKU was recognized, screened for and treated with a low-Phe diet to support cognitive development.

Kwitkin is grateful for the popularity of gluten-free, PKU-friendly products and specialty food stores – compared to when she was growing up and had to order medical bread, which cost $13 a loaf and came out of a can. This trend makes it easy to find PKU-friendly meals to eat.

Expanding her palate is one of the reasons Kwitkin is following the results of a new clinic at Children’s National to help people with PKU experiment with Palynziq, an enzyme substitution therapy that helps people with PKU digest Phe.

Palynziq was approved by the Food and Drug administration on May 24, 2018 and a team of metabolic dietitians and geneticists at Children’s National have been helping a handful of adult PKU patients test out the treatment, slowly, over a preliminary period.

To prescribe the drug in a medically-supervised setting, the doctors introduced the injectable enzyme treatment to participants in small .25-mg doses, which started on Aug. 20, 2018, and monitored their progress as they worked up to the standard 20-mg treatment, a milestone many in the group reached in November 2018.

If the treatment continues to go well, based on the results of the FDA’s recommended titration schedule, the medical team will enroll additional participants in its clinic and share the results with other medical centers.

The timing of the new Palynziq clinic is also perfect for Kwitkin. If the drug works for her in the future, she won’t have to make three dinners: one for her, one for her husband and one for Clara Rose. While Kwitkin is currently off the low-Phe diet, she looks forward to resuming a PKU-friendly diet in the future – especially as she and her husband consider having a second child.

Kwitkin’s PKU-friendly diet consists of “safe” foods, such as unlimited amounts of peaches, apples, cabbage and green beans, which contain zero traces of Phe, and portioned amounts of low-Phe foods: pasta, bread, baked potatoes and specialty-ordered, low-protein items.

While planning for pregnancy, Kwitkin adjusted her protein intake to eight grams of protein a day. During pregnancy, she ate up to 19 grams of daily protein – to satiate her body’s needs and the needs of her baby – and regularly checked in with Erin MacLeod, Ph.D., a metabolic dietitian at Children’s National who is guiding the Palynziq clinic.

Kwitkin-family-photo

Ashley Kwitkin and her husband look forward to expanding their family in the future.

While the new Palynziq therapy carries potential benefits, such as the ability to join a family potluck without counting grams of protein, have second servings of broccoli, a carefully-portioned vegetable on the PKU diet, or thinking clearly while eating a low-Phe diet, a motivating factor for many of MacLeod’s patients, the treatment also carries risks. 

Potential side effects of Palynziq include severe allergic reactions – swelling of the face, lips, eyes and tongue – as well as shortness of breath, a faster heart rate, rashes, confusion, lightheadedness, nausea and vomiting.

So far, minor side effects, such as rashes and injection-site soreness, are noted among participants in the Palynziq trial at Children’s National. The full 20-mg prescription could be increased or decreased, based on how a person’s immune system responds to the foreign agent. If all continues to go well for the participants, they will take the recommended dose, equivalent to about 20 injections a week, and check in with the medical team every three months during the first year. Based on their benefit-risk assessment of the new drug, they can then segue into bi-annual visits if they want to continue with the treatment.  

“Our goal is to help participants decide if this therapy is a good fit for them, based on their lifestyle and health preferences,” notes MacLeod. For some people, MacLeod explains, such as those entering college or who form strong social connections around food, and who may experience the impact of going ‘off diet,’ this treatment could change their lives. Others, such as those who are in the process of moving to a new city or are in a busy period of their lives, may prefer following a strict low-protein diet compared to taking daily enzyme injections.

Another factor Kwitkin and MacLeod will keep in mind as the Palynziq clinics advance is the treatment’s variability. For example, Kuvan, the first drug of its kind is an enzyme therapy developed to help the body break down Phe. The drug was approved by the FDA in 2007, but only works in a small portion of the PKU population – about 10 percent of patients with a mild form of the condition. Instead of eating high-Phe foods, Kuvan users follow a mild-protein diet.

MacLeod views this type of individualized meal planning and how her patients react to food as a science, which drew her to the field. She works with 70 to 100 PKU patients each year from infancy to adulthood, including patients in their 60s, to help them meet their unique metabolic needs.

MacLeod is also tracking the use of gene therapy in metabolic disorders in addition to how the gut flora, or gut bacteria, helps PKU patients modulate and break down Phe.

“A lot of research is happening right now,” adds MacLeod about accelerations with PKU therapy. “I’ve seen how patients respond to new treatments, including a carefully-measured, low-Phe diet, and how their lives start to change once they can think clearly and feel better, which is a motivating factor and goal for many of our patients. I’ve also seen others pursue their dreams, which in Kwitkin’s case was to become a parent and history teacher.”

Like Kwitkin and others impacted by PKU, MacLeod looks forward to ongoing developments and research for this rare disease.

 

Sen Chandra Sreetama and Jyoti K Jaiswal

Modified glucocorticoid stabilizes dysferlin-deficient muscle cell membrane in experimental models

Sen Chandra Sreetama and Jyoti K Jaiswal

Limb girdle muscular dystrophy type 2B (LGMD2B) – a disease so rare that researchers aren’t even sure how many people it affects – is characterized by chronic muscle inflammation and progressively weakened muscles in the pelvis and shoulder girdle. It can affect able-bodied people during their childbearing years and makes it difficult to tiptoe, walk, run or rise unaided from a squat. Ultimately, many with the muscle-wasting condition require wheelchair assistance. There is no therapy approved by the Food and Drug Administration for this condition.

In a head-to-head trial between the conventional glucocorticoid, prednisolone, and a modified glucocorticoid, vamorolone, in experimental models of LGMD2B, vamorolone improved dysferlin-deficient muscle cell membrane stability and repair. This correlated with increased muscle strength and decreased muscle degeneration, according to a Children’s-led study published online Aug. 27, 2018, in Molecular Therapy. By contrast, prednisolone worsened muscle weakness, impaired muscle repair and increased myofiber atrophy.

“These two steroids differ by only two chemical groups,” says Jyoti K. Jaiswal, MSC, Ph.D., a principal investigator at Children’s National Health System and senior study author. “One made muscle repair better. The other made muscle repair worse or about the same as untreated experimental models. This matches experience in the clinic as patients with LGMD2B experienced increased muscle weakness after being prescribed conventional glucocorticoids, such as prednisolone.”

Healthy muscle cells rely on the protein dysferlin to properly repair the sarcolemmal membrane, a cell membrane specialized for muscle cells that serves a vital role in ensuring that muscle fibers are strong enough and have the necessary resources to contract. Mutations in the DYSF gene that produces this essential protein causes LGMD2B.

Jaiswal likens the plasma membrane to a balloon that sits atop the myofiber, a long cell that when healthy can flex and contract. If, in the process of myofiber contraction, the plasma membrane experiences anything out of sync or overly stressful, it develops a tear that needs to be quickly sealed. An intact balloon keeps air inside; tear it, and air escapes. When the plasma membrane tears, calcium from the outside leaks in, causing the muscle cell to collapse into a ball and die. The body contends with the dead cell by breaking it up into fragments and sending in inflammatory cells to clear the debris.

Lack of dysferlin is associated with increased lipid mobility in the LGMD2B cell membrane

Lack of dysferlin is associated with increased lipid mobility in the limb girdle muscular dystrophy type 2B (LGMD2B) cell membrane, which is further increased by injury and prednisolone treatment, causing failure of these cells to undergo repair. By contrast, vamorolone treatment stabilizes the LGMD2B muscle cell membrane to near healthy cell level, enabling repair of injured cells.

The study team got the idea for the current research project during a previous study of the experimental treatment vamorolone for a different type of muscular dystrophy. “In Duchenne muscular dystrophy (DMD), treatment with vamorolone not only reduced inflammation, but the membranes of muscle fibers were stabilized. That was the team’s ah-hah moment,” he says.

Three different doses of vamorolone were tested on cells derived from patients with LGMD2B with higher cell membrane repair efficacy seen with rising treatment dose. The dysferlinopathic experimental models were treated for three months with daily doses of cherry syrup laced with either 30 mg/kg of vamorolone or prednisolone or cherry syrup alone as the placebo arm.

“Right now there are zero treatments,” he says. People with LGMD2B turn to rehabilitative therapies and movement aids to cope with loss of mobility. Doctors are cautioned not to prescribe steroids. Jaiswal says many patients with LGMD2B grew up doing strenuous exercise, former athletes whose first indication of a problem was muscle cramping and pain. How this progresses to muscle weakness and loss is an area of active research in Jaiswal’s lab. “While additional research is needed, our findings here suggest that modified steroids such as vamorlone may be an option for some patients,” Jaiswal says.

“There is a nuance here: In addition to genomic effects, steroids also have physical effects on the cell membrane which may make some of the approved steroids ‘good’ steroids for dysferlinopathy that could selectively be used for this disease,” adds Sen Chandra Sreetama, lead study author.  Further research could indicate whether vamorolone, which is in Phase II human clinical trials for DMD, or any off-the-shelf drug could slow decline in muscle function for patients with LGMD2B.

Additional Children’s study authors include Goutam Chandra; Jack H. Van der Meulen; Mohammad Mahad Ahmad; Peter Suzuki; Shivaprasad Bhuvanendran; and Kanneboyina Nagaraju and Eric P. Hoffman, both of ReveraGen BioPharma.

Research reported in this news release was supported by the Clark Charitable Foundation; Muscular Dystrophy Association, under award number MDA277389; National Institute of Arthritis and Musculoskeletal and Skin Diseases, under award number R01AR055686; National Institutes of Health (NIH), under award numbers K26OD011171 and R24HD050846; and the District of Columbia Intellectual and Developmental Disabilities Research Center under NIH award number 1U54HD090257.