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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.

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.