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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.

Biomarkers sensitive to daily corticosteroid use

Using a mass spectrometer, Yetrib Hathout, Ph.D., is able to quantify 3,000 to 4,000 proteins from a tissue sample to identify proteins associated with cancer.

Using a Somascan proteomics assay – which simultaneously analyzes 1,129 proteins in a small volume of serum – a team led by Children’s National Health System researchers identified 21 biomarkers that respond to corticosteroids taken daily by children with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease.

Corticosteroids are commonly prescribed to treat inflammatory conditions. High daily doses of corticosteroids are considered the standard of care for DMD, a type of muscular dystrophy characterized by worsening muscle weakness that affects 1 in 3,600 male infants. However, depending on the age of the child and drug dosage, chronic use is associated with such side effects as changes in bone remodeling that can lead to stunted growth, weight gain, facial puffiness caused by fat buildup, mood changes, sleep disturbances, and immune suppression. The research team sought to identify blood biomarkers that could be leveraged to create a fast, reliable way to gauge the safety and efficacy of corticosteroid use by children. The biomarkers also could guide development of a replacement therapy with fewer side effects.

“Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG),” Yetrib Hathout, Ph.D., Proteomic Core Director at Children’s National, and colleagues write in the journal Scientific Reports. “These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids.”

The blood biomarkers sensitive to corticosteroids fit into three broad groups, according to the authors. The children taking corticosteroids were matched with children of the same age who had never taken the medicine. Five biomarkers significantly increased in this corticosteroid-naïve group and decreased in kids prescribed corticosteroids. The biomarkers generally were inflammatory proteins and included chemokine, insulin-like growth factor binding protein 2, and integrin alpha-I/beta-1 complex.

The second group of biomarkers included nine proteins associated with macrophage and T-lymphocytes that were significantly reduced in concentration in kids taking corticosteroids. According to the study, this finding hints at corticosteroids blunting the ability of the immune system’s most able fighters to respond to infection.

In the third group were five proteins that were significantly increased by corticosteroid treatment in DMD and included matrix metalloproteinase 3, carnosine dipeptidase 1, angiotensinogen, growth hormone binding protein, insulin, and leptin, a hormone linked to appetite.

What researchers learned with this study will help them more accurately design the next phase of the work, Hathout says.

“We are the first team to report a number of novel discoveries, including that growth hormone binding protein (GHBP) levels increase with corticosteroid use. This represents a candidate biomarker for stunted growth. In order to use that new information effectively in drug development, the next studies must corroborate the role of serum GHBP levels as predictors of diminished stature,” he adds. “The study finding that four adrenal steroid hormones are depressed in kids taking corticosteroids raises additional questions about the broader impact of adrenal insufficiency, including its role in the delay of the onset of puberty.”

This work was supported by National Institutes of Health grants (R01AR062380, R01AR061875, P50AR060836, U54HD071601, K99HL130035, and R44NS095423) and Department of Defense CDMRP program grant W81XWH-15-1-0265. Additional support was provided by AFM-Telethon (18259) and the Muscular Dystrophy Association USA (MDA353094).