Viral vectors for gene transfer of micro-, mini-, or full-length dystrophin

Scott, Jeannine M.; Li, Sheng; Harper, Scott Q.; Welikson, Robert E.; Bourque, Daniel; DelloRusso, Christiana; Hauschka, Stephen D.; Chamberlain, Jeffrey S.

doi:10.1016/s0960-8966(02)00078-0

Cited by 79 publications

(42 citation statements)

References 38 publications

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“…The use of animal models of muscular dystrophy with a functional dystrophin and DGC complex, 10 as well as dystrophin-overexpressing mdx mice, 25 could help understand the role of dystrophin in neovascularization. Secondary mechanisms, such as the inflammatory response to muscle damage, could be responsible for increased arteriogenesis and regeneration in mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient mdx Mice

et al. 2004

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Background-The absence of functional dystrophin in Duchenne muscular dystrophy (DMD) patients and in mdx mice results in progressive muscle degeneration associated with necrosis, fibrosis, and inflammation. Because vascular supply plays a key role in tissue repair, we examined whether new blood vessel development was altered in mdx mice. Methods and Results-In a model of hindlimb ischemia on femoral artery dissection, hindlimb perfusion, measured by laser Doppler imaging, was higher in mdx mice (0.67Ϯ0.26) than in wild-type (WT) mice (0.33Ϯ0.18, PϽ0.03). In keeping with these data, a significant increase in arteriole length density was found in mdx mice (13.6Ϯ8.4 mm/mm 3 ) compared with WT mice (7.8Ϯ4.6 mm/mm 3 , PϽ0.03). Conversely, no difference was observed in capillary density between mice of the 2 genotypes. The enhanced regenerative response was not limited to ischemic skeletal muscle, because in a wound-healing assay, mdx mice showed an accelerated wound closure rate compared with WT mice. Moreover, a vascularization assay in Matrigel plugs containing basic fibroblast growth factor injected subcutaneously revealed an increased length density of arterioles in mdx (46.9Ϯ14.7 mm/mm 3 ) versus WT mice (19.5Ϯ5.8 mm/mm 3 , PϽ0.001). Finally, serum derived from mdx mice sustained formation of endothelium-derived tubular structures in vitro more efficiently than WT serum.Conclusions-These results demonstrate that arteriogenesis is enhanced in mdx mice both after ischemia and skin wounding and in response to growth factors.

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Section: Discussionmentioning

confidence: 99%

Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient mdx Mice

et al. 2004

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“…[9][10][11][12] However, the MCK promoter is less active than viral promoters, and its large size (6.5 kb) makes it incompatible with adeno-associated viral (AAV) vectors, a noteworthy gene delivery vehicle with a 4.5-kb capacity for the treatment of muscular dystrophies and other degenerative disorders. [13][14][15] We have shown previously that a truncated MCK promoter (enh358MCK, 584-bp) could achieve musclespecific expression of the human minidystrophin genes (3.8-4.2 kb) in dystrophin-deficient mdx mice, ameliorate pathologies and improve muscle contractile function in mdx mice. 15,16 However, the expression activity was less than the CMV promoter seen consistently in studies from other investigators.…”

Section: Instructionmentioning

confidence: 99%

Construction and analysis of compact muscle-specific promoters for AAV vectors

et al. 2008

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Adeno-associated viral (AAV) vectors have been broadly used for gene transfer in vivo for various applications. However, AAV precludes the use of most of the original large-sized tissue-specific promoters for expression of transgenes. Efforts are made to develop highly compact, active and yet tissue-specific promoters for use in AAV vectors. In this study, we further abbreviated the muscle creatine kinase (MCK) promoter by ligating a double or triple tandem of MCK enhancer (206-bp) to its 87-bp basal promoter, generating the dMCK (509-bp) and tMCK (720-bp) promoters. The dMCK promoter is shorter but stronger than some previously developed MCK-based promoters such as the enh358MCK (584-bp) and CK6 (589-bp) in vitro in C2C12 myotubes and in vivo in skeletal muscles. The tMCK promoter is the strongest that we tested here, more active than the promiscuous cytomegalovirus (CMV) promoter. Furthermore, both the dMCK and tMCK promoters are essentially inactive in nonmuscle cell lines as well as in the mouse liver (4200-fold weaker than the CMV promoter).The dMCK promoter was further tested in a few lines of transgenic mice. Expression of LacZ or minidystrophin gene was detected in skeletal muscles throughout the body, but was weak in the diaphragm, and undetectable in the heart and other tissues. Similar to other miniature MCK promoters, the dMCK promoter also shows preference for fast-twitch myofibers. As a result, we further examined a short, synthetic muscle promoter C5-12 (312-bp). It is active in both skeletal and cardiac muscles but lacks apparent preference on myofiber types. Combination of a MCK enhancer to promoter C5-12 has increased its strength in muscle by two-to threefold. The above-mentioned compact muscle-specific promoters are well suited for AAV vectors in muscle-directed gene therapy studies.

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“…The microgene carries only onethird of the dystrophin coding sequence (*4 kb). 64,65 Unlike the D17-48 minigene, there is no human precedent of a functional microgene. Although patients with super-large inframe deletions have been identified and expression of microsize dystrophin has been confirmed in some cases, unfortunately, these patients invariably displayed severe clinical …”

Section: Dystrophin Replacement Therapy In the Cdmd Modelmentioning

confidence: 99%

Duchenne muscular dystrophy gene therapy in the canine model

Duan¹

2015

Human Gene Therapy Clinical Development

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Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model.

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Viral vectors for gene transfer of micro-, mini-, or full-length dystrophin

Cited by 79 publications

References 38 publications

Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient mdx Mice

Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient mdx Mice

Construction and analysis of compact muscle-specific promoters for AAV vectors

Duchenne muscular dystrophy gene therapy in the canine model

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