Becker Muscular Dystrophy (BMD)
MDA-supported investigators are actively pursuing several approaches to halt or reverse the muscle damage caused by Becker muscular dystrophy (BMD).
Some of the front-running strategies include: inserting new dystrophin genes; changing the way cells interpret genetic instructions for creating dystrophin; changing the mutated dystrophin gene itself; manipulating other proteins in the body to compensate for the lack of dystrophin; increasing blood flow to muscles; and using stem cells to repair damaged muscles. Some studies are focused specifically on the dystrophin-deficient heart.
Flaws in the dystrophin gene cause Duchenne muscular dystrophy (DMD), BMD, and an intermediate form of the DMD, so many of the strategies being tried in DMD also apply to BMD.
For more, see these 2012 videos on BMD research: Preclinical Testing in Animal Models of Muscular Dystrophy and From Targets to Clinical Trials in Becker Muscular Dystrophy.
Researchers are pursuing strategies to sustain or improve heart function in BMD and DMD. They're testing existing medications for their possible benefits in the BMD/DMD-affected heart and conducting basic research to understand and find new approaches to treating the heart in these diseases.
Understanding and treating dystrophin-deficient cardiomyopathy (cardiac muscle abnormalities) is a priority for MDA. The MDA DMD Clinical Research Network has made studying the natural history and treatment of this condition a primary focus. In addition, MDA sponsored a meeting of more than 40 leading clinicians and researchers from the United States and Europe to discuss optimal clinical care of the DMD/BMD-affected heart.
Laboratory studies have found that an experimental compound designed to help seal cell membranes, poloxamer 188 (p188), benefited heart function in dystrophin-deficient dogs can increase muscle structural stability and reseal damaged membranes. As result, P188 can improve patient’s clinical prognosis, especially those who diagnosed with DMD/BMD related cardiomyopathy. Despite the great potential, researchers worry that P188 might be toxic for long term applications.1
Because several cardiomyopathy drugs have been developed over the years to treat heart failure in older patients, doctors already have some tools at their disposal for treating the BMD/DMD heart. These therapies center on ways of reducing the burden on the pumping heart. To that end, doctors may prescribe angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) that make blood vessels open wide and thereby reduce the resistance to the heart’s pumping action. Doctors may also prescribe diuretics to remove extra water from the blood so that there is less volume for the heart to pump. Finally, doctors may prescribe beta blockers to slow the heart rate, giving the DMD heart sufficient time to empty and refill with each beat so that it can pump blood more efficiently.
Researchers are continuing to study existing drugs to determine the best regimen to preserve heart function in DMD. Currently, several clinical studies are aimed at determining the best combination and doses of medications to prevent decline of heart function. This includes a phase 3 clinical study led by Dr. Subha Raman at Ohio State University examining the relative efficacy of aldosterone receptor antagonists, including spironolactone and eplerinone, which are diuretics. Prior work by this group demonstrated that treatment with eplerinone (along with ACE inhibitors or ARBs) slowed the decline of cardiac function in boys with DMD over the course of one year.
Additional studies investigating the optimal drug regimen for slowing cardiac decline in DMD include a phase 4 study in Italy comparing the effects of carvedilol (a beta blocker) with ramipril (an ACE inhibitor), and a phase 3 study in France examining the effects of nebivolol (a beta blocker).
One promising and completely new therapy in development specifically for DMD is called CAP-1002 and is being developed by Capricor Therapeutics. CAP-1002 is a therapy based on cardiac stem cells derived from donor heart tissue. Researchers aim to transplant these therapeutic stem cells into people with DMD with the hope that the cells will promote muscle tissue regeneration. Currently, Capricor is conducting a clinical trial to evaluate the potential ability of CAP-1002 to benefit skeletal muscle function in boys and young men with DMD. In July 2019, Capricor Therapeutics released interim efficiency and adverse events data form the phase 2 clinical trials (HOPE-2). Capricor Therapeutics reported improved clinically relevant outcomes including upper limb, hand and diaphragmatic strength. In December 2018, Capricor put a voluntary hold on dosing after two patients in the HOPE trials had a serious adverse event in the form of an immediate immune reaction. As a result, Capricor initiated pretreatment regimen including anti-histamines and steroids, to reduce the chance for severe side-effects. Consequently, in HOPE-2, only one serious side effect was observed and required overnight observation
Another new therapy called PB1046 is in development by PhaseBio Pharmaceuticals. PB1046 is an engineered version of vasoactive intestinal peptide (VIP), a neuropeptide that has been shown to be ionotropic (increases contraction of the heart) and lusitropic (speeds relaxation of the heart). VIP also has been shown to prevent fibrosis and inflammation in cardiac and skeletal muscle. PhaseBio has reported that its engineered version of VIP, PB1046, slowed cardiac functional deterioration in two mouse models of DMD and showed positive safety data in a clinical trial with volunteers who had essential hypertension. Currently, PhaseBio is in phase 2 clinical trials for DMD patients.
Although still in very early stages of development, repair of the dystrophin gene at the DNA level shows promise. This strategy is aimed at helping cells permanently repair errors in the dystrophin gene, fixing the underlying cause of DMD.
In experiments on cultured cells and in mice with flawed dystrophin genes, "designer" gene-repair molecules stimulated DNA repair levels more than 10 times the repair levels achieved by a previous class of targeting molecules. The muscle cells containing rejuvenated dystrophin genes successfully produced normal dystrophin protein at levels consistently higher than muscle cells treated with the older-generation molecules.
Although the results so far have been encouraging, the frequencies of gene repair are in the 1 to 5 percent range — too low to be considered therapeutically relevant. And, for now, the gene repair strategy is limited to correcting "single-letter" errors (point mutations) in a gene.
Similar experiments are being done using CRISPR/CAS-9 gene-editing technics. Researchers have been using the therapy to try to develop a treatment that repairs deletions in the DMD gene and have had promising results in several animal models and in cells donated by patients. Unfortunately, many hurdles remain, preventing researchers from advancing into clinical trials.2
Work must be done before this technique can progress to human trials, including refinement of the targeting molecules, studies to determine the most effective delivery methods, and testing in different animal models.
Gene transfer therapy
Gene transfer refers to the delivery of genes as therapeutic agents. Because genes carry the instructions for protein synthesis, they can lead to production of proteins that are directly or indirectly therapeutic in neuromuscular diseases. Because transferred genes potentially can continue to produce protein for some time, gene therapy may offer a more permanent fix than other therapies. But gene therapy faces many technical challenges, as well as a high bar set by regulatory agencies like the U.S. Food and Drug Administration (FDA).
To accomplish gene transfer in DMD, researchers use the action of viruses. A virus works by inserting its own genetic material into a host, which causes the host’s cells to manufacture viral proteins. Researchers can incorporate a gene of interest into a virus and “instruct” the virus (a viral vehicle) to produce protein in excess. This method can be used to manufacture functional dystrophin in the muscle of patients with DMD and other neuromuscular diseases. To accomplish this without making patients sick, scientists are utilizing viruses that do not cause illness in humans. The benefit of this approach remains to be proven effective in patients with BMD.
The key challenges are delivering the genes to the targeted tissue while avoiding off-target tissues and avoiding unwanted immune response to the proteins made from the new genes, or to the delivery vehicles (viruses).
MDA-supported scientists have created a miniaturized, working dystrophin gene that has been tested in boys with DMD. Although the treatment appeared to be safe, some of the boys experienced an unwanted immune response to the dystrophin protein that limited the effectiveness of the gene transfer. This immune response is undergoing further investigation.
Increasing blood flow to muscles
Experiments have shown that, when dystrophin is missing from the muscle-fiber membrane, it causes another protein, known as nNOS, to be missing as well. This results in an inability of blood vessels supplying muscles to adequately dilate during exercise. When nNOS-deficient mice were treated with a phosphodiesterase inhibitor, which dilates blood vessels, their exaggerated fatigue response to exercise was eliminated. Phosphodiesterase inhibitors are a class of drugs that include sildenafil (Viagra) and tadalafil (Cialis), both used to treat erectile dysfunction.
Other investigators found that treatment with sildenafil significantly improved heart function in mice missing the dystrophin protein.
On the basis of these and other findings, researchers have started investigating the possibility that phosphodiesterase inhibitors can improve skeletal-muscle or heart-muscle function in people with BMD or DMD.
A strategy that has received considerable MDA support involves inhibiting the actions of a naturally occurring protein called myostatin, which limits muscle growth. Researchers hope that blocking myostatin may allow muscles to grow larger and stronger.
Myostatin inhibitors have received much attention from the neuromuscular disease research community since the discovery several years ago that people and animals with a genetic deficiency of myostatin appear to have large muscles and good strength without apparent ill effects.3
Currently, Pfizer is developing a myostatin inhibitor called PF-06252616 (domagrozumab), which is in clinical trials to test its effectiveness in boys with DMD. Bristol-Myers Squibb also is developing a myostatin inhibitor drug, BMS-986089 (talditercept alfa). This potential therapy is currently in a phase 2/3 study. In addition to these two potential DMD medicines, Eli Lilly (LY2495655), Regeneron (REGN1033), and Novartis (BYM338) also are developing drugs that inhibit myostatin, but these are being tested in clinical studies for their effects in cancer wasting (cachexia), sarcopenia, and inclusion-body myopathy (IBM), respectively.
Another unique strategy to block the action of myostatin uses gene therapy to introduce follistatin, a naturally occurring inhibitor of myostatin. Mice with a DMD-like disease that received genes for the follistatin protein showed an overall increase in body mass and weight of individual muscles. Furthermore, monkeys that received follistatin gene transfer had stronger, larger muscles. A gene therapy for delivering follistatin to people with DMD called rAAV1.CMV.huFollistatin344 is being developed by Milo Biotechnology. This potential therapy has been tested so far in an early-stage clinical trial.
MDA scientists are using stem cells (cells from which specialized cells "stem") isolated from muscle, blood vessels, or bone marrow to regenerate muscles in dystrophin-deficient laboratory animals.
Stem cells are cells in the very early stages of development. They may be destined to turn into a specific cell type (such as muscle or nerve cells), or they may still retain pluripotency — the ability to develop into any of a number of different cell types.
A European research group successfully used a combination of genetic correction and stem cells to treat DMD research mice. The researchers in this study extracted muscle-generating stem cells from muscle tissue and blood in people with DMD, corrected the genetic error in the cells' dystrophin genes, and then injected the cells into dystrophin-deficient mice. The muscle-derived cells gave rise to better muscle regeneration than did the blood-derived cells. Some researchers are continuing to study muscle satellite cells, a type of stem cell present in muscle tissue. Other researchers are studying different cell types that are capable of surviving transplantation into muscle and producing the desired proteins.
Stop codon read-through
In stop codon read-through, drugs target mutations known as premature stop codons (also called nonsense mutations), which tell a cell to stop making a protein — for instance, dystrophin — before it has been completely assembled. The drugs coax cells to ignore, or "read through," this improper stop signal. Premature stop codons in the dystrophin gene cause DMD more often than they do BMD, but either disease is possible.
Ataluren (also known as PTC124) is a drug that is being developed for the treatment of genetic defects caused by nonsense (stop) mutations allowing continuation of the translation process to production of a protein. This approach could benefit around 10% to 15% of patients with DMD/BMD who harbor nonsense (stop) mutations. Currently, the drug is approved in the European Union (EU) member states, Iceland, Liechtenstein, Norway, Israel, and South Korea under the trade name Translarna.
The most common adverse effect of ataluren is vomiting. Others include decreased appetite, weight loss, headache, hypertension, cough, nose bleeding, nausea, upper abdominal pain, flatulence, abdominal discomfort, constipation, rash, limb pain, musculoskeletal chest pain, blood in urine, involuntary urination, and fever.
Laboratory evidence shows that raising levels of the muscle protein utrophin can, to some extent, compensate for a deficiency of dystrophin.
Utrophin closely resembles dystrophin but, unlike dystrophin, is normally produced and entirely functional in BMD. Therefore, raising utrophin levels is unlikely to provoke an unwanted immune response, while raising levels of dystrophin may do so. Increasing utrophin production has the potential to help compensate for dystrophin deficiency regardless of the specific dystrophin gene mutation. Some researchers claim that the combination of utrophin and dystrophin therapies might be even more beneficial for muscle function in patients. However, currently it has been tested only in animal models.4
Although utrophin is close to dystrophin in both structure and function, there’s at least one key difference between the two proteins. During fetal development and perhaps a little beyond, utrophin is present all around the muscle fiber, interacting with clusters of proteins stuck in its surrounding membrane. As an animal or person matures, utrophin is replaced almost entirely by dystrophin, with one exception. At the neuromuscular junction, utrophin remains throughout life.
- Moloughney, J. G. & Weisleder, N. Poloxamer 188 (p188) as a membrane resealing reagent in biomedical applications. Recent Pat. Biotechnol. (2012).
- Robinson-Hamm, J. N. & Gersbach, C. A. Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy. Human Genetics (2016). doi:10.1007/s00439-016-1725-z
- Wagner, K. R. & Cohen, J. S. Myostatin-Related Muscle Hypertrophy. GeneReviews (2013).
- Guiraud, S. et al. The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy. Hum. Mol. Genet. (2019). doi:10.1093/hmg/ddz049