Developments in gene therapy for muscular dystrophy

Abstract

Gene therapy for muscular dystrophy (MD) presents significant challenges, including the large amount of muscle tissue in the body, the large size of many genes defective in different muscular dystrophies, and the possibility of a host immune response against the therapeutic gene. Overcoming these challenges requires the development and delivery of suitable gene transfer vectors. Encouraging progress has been made in modifying adenovirus (Ad) vectors to reduce immune response and increase capacity. Recently developed gutted Ad vectors can deliver full‐length dystrophin cDNA expression vectors to muscle tissue. Using muscle‐specific promoters to drive dystrophin expression, a strong immune response has not been observed in mdx mice. Adeno‐associated virus (AAV) vectors can deliver small genes to muscle without provocation of a significant immune response, which should allow long‐term expression of several MD genes. AAV vectors have also been used to deliver sarcoglycan genes to entire muscle groups. These advances and others reviewed here suggest that barriers to gene therapy for MD are surmountable. Microsc. Res. Tech. 48:223–238, 2000. © 2000 Wiley‐Liss, Inc.

Differential signaling through NFκB does not ameliorate skeletal myoblast apoptosis during differentiation

“…NFκB signaling now represents a pathway capable of inhibiting differentiation without inhibiting the associated apoptosis. Despite advances which minimize immune responses [43,44], myoblast therapy as an approach to the treatment of inherited muscular dystrophies is still severely impaired by the poor survival of transplanted myoblasts [45,46]. Identification of a signaling pathway(s) that does not affect differentiation but that does inhibit the apoptosis associated with differentiation should prove useful.…”

Dystrophin Delivery in Dystrophin-Deficient DMDmdxSkeletal Muscle by Isogenic Muscle-Derived Stem Cell Transplantation

“…Observation of a number of mildly affected patients with BMD bearing large in-frame deletions-including one patient displaying an absence of over 40% of the central rod domain of the dystrophin gene-suggests that a functional mini-dystrophin gene could alleviate the DMD phenotype (England et al, 1990). Gene therapy studies based on viral and nonviral vectors have been performed to evaluate delivery of both the full-length dystrophin and many versions of mini-dystrophin genes extensively to assuage the muscle weakness commonly observed in mdx mice (Acsadi et al, 1996;Hauser et al, 1997;Akkaraju et al, 1999;Chapdelaine et al, 2000;Hartigan-O'Connor and Chamberlain, 2000;Wang et al, 2000;Campeau et al, 2001;Gilbert et al, 2001;Fabb et al, 2002;Gilchrist et al, 2002;Harper et al, 2002;Larochelle et al, 2002;Scott et al, 2002;Watchko et al, 2002).…”

Muscular Dystrophy Meets the Gene Chip

“…However, the present data have already provided numerous new insights that will immediately aid studies of the disease pathogenesis. These data should also lead to a variety of new targets to treat secondary pathological features of the diseases, and may well provide a generalized method to monitor the efficacy of such interventions, which might be used either singly or in combination with cell and gene based therapies (Hartigan-O'Connor and Chamberlain 2000). Finally, as Chen et al 2000 note, these approaches may also serve as a basis for differential diagnosis of the many types of muscular dystrophy by enabling test of specific molecule signatures associated with each individual primary genetic defect.…”