Treatments for muscular dystrophy: Increased treatment options for Duchenne and related muscular dystropies

The last few years have been an exciting time for all those committed to developing treatments for muscular dystrophies with the emergence of a number of clinically applicable treatments. The recent paper by Millay et al.¹ makes an important contribution as it opens up a new area of disease modification by reducing mitochondrial-dependent necrosis to alleviate the effects of muscular dystrophy in mice. Potentially, this could also be helpful for other conditions involving mitochondrial-dependent necrosis.

Muscular dystrophies are a group of inherited disorders characterized by progressive muscle wasting often presenting in early childhood. The most common is Duchenne muscular dystrophy (DMD), which affects 1 in 3500 male births. DMD is caused by defects in the largest gene in the human genome, which spans 2.5 Mb. This gene encodes a large cytoskeletal protein called dystrophin that links the cytoskeleton, and hence contractile apparatus, of the muscle cell with the extracellular matrix. Dystrophin is attached to the cytoskeleton by its amino terminus and through a region close to the carboxy terminus to β-dystroglycan embedded in the cell membrane. This in turn links to α-dystroglycan and hence to proteins in the extracellular matrix including laminin α2. A complex of membrane associated proteins (sarcoglycans) is linked to the stabilised β-dystroglycan. A deficiency in any one of the associated or linking proteins causes muscular dystrophy (reviewed in²).

Current treatments for DMD are symptomatic and significantly improve longevity and quality of life but do little to prevent loss of muscle function. Experimental therapies currently under investigation fall into three categories. The first restores expression of dystrophin to halt progression of the disease and a number of approaches modify processing of the gene or introduce a recombinant version of dystrophin. These include antisense-mediated exon-skipping, read-through of premature stop mutations and viral gene transfer, which are all currently at clinical trial stage.^{3, 4} The second involves overexpression of compensating genes either through gene transfer or by upregulating expression using small molecules. Genetic candidates include utrophin, the autosomal homologue of dystrophin, α7 integrin and IGF-1.² The final category involves modifying the disease process downstream of the dystrophin deficiency and a number of disease-modifying agents such as angiotensin II type 1 receptor blockade (Losartan), a blockade of TNF-α and coenzyme Q10 have been tested and shown to be effective in the mouse model of DMD.^{5, 6} The results presented by Millay et al.¹ are an important addition to this latter category and present a novel treatment target.

In many muscular dystrophies the missing protein leads to a destabilization of the sarcolemma with an associated increase in the influx of calcium ions into the muscle fibre. In an effort to remove the excess calcium the mitochondria become overloaded, which triggers an increase in mitochondrial permeability. If left unchecked, this leads to necrotic and/or apoptotic cell death. An important regulator of this process is Cyclophilin D and mice lacking the gene for this protein (Ppif) are resistant to calcium-induced swelling and ischemia/reperfusion-induced cell death.⁷ Millay et al. demonstrate that crossing these Ppif^−/− mice with mice lacking δ sarcoglycan (Scgd^−/−, a mouse model of limb girdle muscular dystrophy 2F) or laminin α2 (Lama2^−/−, a mouse model of congenital muscular dystrophy 1A), markedly attenuated the disease process, although it did not prevent it entirely.¹ They also showed that two times daily treatment for 6 weeks with Debio-025, a cyclophilin inhibitor, substantially reduced the disease in mdx and Scgd^−/− mice.

Debio-025 is a synthetic cyclosporine analogue with no immunosuppressive capacity but a high inhibitory potency against cyclophilin A-associated cis–trans prolyl isomerase activity. It is under development by the Debiopharm Group as a treatment for hepatitis C and has recently completed a Phase IIa clinical trial (http://www.debiopharm.com/products/pipeline/debio-025.html). The results of the Millay paper suggest that the use of Debio-025 offers new treatment strategies for muscular dystrophies including DMD; however, it is important to be cautious in extrapolating directly from mouse to man. A key concern would be the determination of a safe and effective dose of Debio-025 in man. Most pre-clinical studies essentially dose for effect whereas human doses are necessarily driven by safety issues rather than maximum effectiveness. Furthermore, any successful treatment for muscular dystrophies is likely to require continuous or repeated cycles of treatment and little is known about the long-term toxicity in man of many of the therapies that have been acutely tested in mouse models. Finally, mice may not be the best model of the disease. In the case of DMD, it would be very interesting to see the results of using Debio-025 in the canine model, the golden retriever muscular dystrophy. GRMD dogs have a more severe disease than mdx mice with a marked reduction in mobility and premature death. This happens during the first year of the dog's life and will therefore allow clinical assessment of the benefit of a therapeutic approach.

Despite these reservations, the reduction of mitochondrial-dependent necrosis is an important addition to the range of potential treatments for DMD and related muscular dystrophies. It is likely that no single treatment will be sufficient to completely halt or reverse the progression of these diseases but a combination of treatments may one day provide the answer to these devastating conditions.