Duchenne muscular dystrophy, which generally affects males, is caused by a mutation in a gene called dystrophin. DMD causes generalized weakness and muscle wasting first affecting the muscles of the hips, pelvic area, thighs and shoulders. Calves often are enlarged. DMD eventually affects all voluntary muscles, and the heart and breathing muscles. A less severe variant is Becker muscular dystrophy (BMD).
Since MDA-sponsored researchers found that DMD and BMD are caused by mutations in a specific gene called dystrophin in 1986, research into the diseases has flourished. In the last decade, this research has resulted in an explosion of potential treatments, many of which are now in preclinical development or in clinical trials.
As of 2013, more than 30 pharmaceutical and biotechnology companies and academic researchers have treatments under development for DMD. Strategies for treating the disease include:
- Glucocorticoids, such as prednisone, are standards of care for DMD, but there is a lot of research into ways of reducing the side effects of such compounds by changes to the drug itself, or by changing the dosing regime.
- Correction of specific mutations is being attempted in several ways by different groups. “Nonsense mutations,” or early stop signals, in the gene can be ignored in the presence of some drugs in development, whereas other flawed regions of the gene can be “skipped” allowing for the formation of functional protein.
- Gene-replacement techniques, such as gene therapy to replace the flawed dystrophin have shown some success in DMD.
- Cell therapies aim to replace dystrophin with protein produced from the donor cells.
- Upregulation of proteins similar to dystrophin (such at utrophin) that may be able to act in its place.
- Strategies to increase strength in dystrophic muscle, such as by inhibition of myostatin.
- Cardiomyopathy therapies to treat the cardiac issues that are associated with DMD.
- Anti-fibrotics that are designed to reduce the damage caused to DMD muscles over time.
- Anti-inflammatory therapies aim to reduce muscle damage and may have additional effects.
Translational Research: DMD Projects with Promise
The MDA Translational Research Program's first project provided $1.5 million to Asklepios BioPharmaceutical to perform a phase 1 study of a gene therapy technique that resulted in muscle producing small amounts of dystrophin. This company, with an additional $2.5 million from MDA, continued to develop this technique, and is now progressing toward later-stage trials.
MDA's Translational Research Program also funded a $1.5 million grant that supported an initial trial for ataluren (PTC124), a small molecule drug developed by PTC Therapeutics that causes cells to “ignore” one type of mutation that causes DMD.
With the formation of MVP, MDA invested in several additional DMD programs:
- MVP awarded Catabasis Pharmaceuticals $150,000 for a pilot project to see if Catabasis' novel anti-inflammatory drug affects symptoms in a mouse model of DMD. In 2013, MVP awarded $120,000 for further studies that, if successful, will result in clinical trials of the compound.
- MVP awarded ReveraGen BioPharma $360,000 for a project to optimize compounds with the same positive effects as prednisone but without the side effects. Prednisone is well-established as a therapy for DMD and prolongs walking in patients, but the therapy has significant side effects. MVP funds were used to manufacture the potential drug and confirm its action in an animal model. In 2013, MVP awarded $1.5 million to ReveraGen that, in partnership with the NIH TRND program, will allow the company to bring the drug to the point of clinical trials.
- MVP awarded Carmen Bertoni at the University of California, Los Angeles $476,465 to develop RTC#13 or one of its derivatives for the treatment of Duchenne muscular dystrophy. This is a drug designed to read through specific mutations, called "nonsense mutations" which cause some DMD cases, and shows promise in cell and mouse models of the disease.
- MVP awarded $1.5 million to Acceleron Pharma to continue a phase 2 trial of ACE-031, the company’s myostatin inhibitor that may increase muscle strength in DMD patients. This trial is currently on hold due to possible safety concerns, and MVP has ceased funding the project due to failure to meet the agreed upon milestones.
- MVP awarded $750,000 to Summit Plc to reformulate a drug that upregulates utrophin, a protein that is thought to be able to replace dystrophin, and to get the drug back into phase 1 trials.
- MVP awarded $1M to ARMGO Pharma to develop a calcium channel drug for DMD. This drug is likely to be effective in multiple diseases in MDA’s program.