Treating Muscular Dystrophy with Membrane Resealing
Dongsheng Duan, PhD
Posted: April 6, 2012

Enhancing Muscle Membrane Repair by Gene Delivery of MG53 Ameliorates Muscular Dystrophy and Heart Failure in delta-Sarcoglycan-deficient Hamsters
Bo He, Ru-hang Tang, Noah Weisleder, Bin Xiao, Zhenhua Yuan, Chuanxi Cai, Hua Zhu, Peihui Lin, Chunping Qiao, Jianbin Li, Christina Mayer, Juan Li, Jianjie Ma, Xiao Xiao

A quintessential feature of muscular dystrophy is sarcolemmal tear. Strategies that enhance endogenous membrane repair may thus be utilized to treat muscular dystrophy. The prevailing theory of membrane repair is called “patch hypothesis.” Based on this model, membrane disruption triggers formation and translocation of membrane repairing vesicles to the injury site. Through a dysferlin and annexin-mediated process, these vesicles merge into one large vesicle. Eventually membrane wounds are patched up by the fused vesicle ¹. Mitsugumin 53 (MG53), a muscle specific tripartite motif family protein, contributes to membrane repair by facilitating vesicle trafficking². By analogy, it is expected that increasing MG53 level may boost membrane repair and hence mitigate muscular dystrophy. In a recent paper published in Molecular Therapy, He et al tested this hypothesis in d-sarcoglycan null hamsters, a model of limb girdle muscular dystrophy 2F (LGMD2F)³. The authors delivered a MG53 adeno-associated viral vector (AAV) to either newborn puppies or young adult hamsters. Supra-physiological levels of MG53 expression were achieved in limb muscles and the heart. In both age groups, AAV MG53 therapy partially reduced the serum creatine kinase level, stabilized sarcolemma, and slowed down muscle degeneration and fibrosis. Further, the treated animals showed improved performance in a treadmill assay and their heart function was also enhanced according to echocardiography examination. The authors further showed that disease amelioration was accompanied with beneficial changes of cell survival signals.

MG53-based therapy may have some advantages. Since the therapeutic gene product is a self-protein, it may less likely induce strong immune rejection. Another appealing aspect of MG53 therapy is the possibility of “one pill for all.” The MG53 approach is aimed at membrane disruption, a pathological process seen in essentially every type of muscular dystrophy irrespective of its genetic underpinning. The only exceptions would be these caused by dysferlin deficiency (such as LGMD2B, Miyoshi muscular dystrophy and tibial muscular dystrophy) because dysferlin is required for vesicle-mediated membrane resealing⁴.

Despite the rosy outlook, there are several important concerns. The most significant issue is the toxicity. He at el noticed that even trivial (leaky) expression in the liver-caused hepatic injury (as reflected by elevation of serum alanine transaminase), growth retardation and reduced treadmill running³. Although several technologies (such as viral capsid engineering, the development of the tissue specific promoter and incorporation of microRNA target sequences in the expression cassette) have been developed to minimize untoward expression in non-target tissues, the toxicity remains a valid concern if one considers the fact that trillions of viral particles may be required to treat a single patient.

Caution should also be taken on our expectations of the therapeutic efficacy⁵. Vitamin E has been shown to promote membrane repair⁶. Yet, vitamin E supplementation has not resulted in clear benefit in muscular dystrophy patients⁷.
 

References

1. McNeil, PL, and Steinhardt, RA (2003). Plasma membrane disruption: repair, prevention, adaptation. Annu Rev Cell Dev Biol 19: 697-731.

2. Cai, C, et al. (2009). MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol 11: 56-64.

3. He, B, et al. (2012). Enhancing Muscle Membrane Repair by Gene Delivery of MG53 Ameliorates Muscular Dystrophy and Heart Failure in delta-Sarcoglycan-deficient Hamsters. Mol Ther.

4. McNeil, P (2009). Membrane repair redux: redox of MG53. Nat Cell Biol 11: 7-9.

5. Mullard, A (2011). Reliability of 'new drug target' claims called into question. Nat Rev Drug Discov 10: 643-644.

6. Howard, AC, McNeil, AK, and McNeil, PL (2011). Promotion of plasma membrane repair by vitamin E. Nat Commun 2: 597.

7. Rando, TA (2002). Oxidative stress and the pathogenesis of muscular dystrophies. Am J Phys Med Rehabil 81: S175-186.