Herpes simplex virus VP22 enhances adenovirus-mediated microdystrophin gene transfer to skeletal muscles in dystrophin-deficient (mdx) mice.
One of the obstacles to efficient vector-mediated gene therapy for Duchenne's muscular dystrophy (DMD) is its limited transduction efficiency. The VP22 tegument protein of herpes simplex virus type 1 (HSV-1) is able to cross biological membranes and translocate the VP22 fusion protein from transfected primary cells to surrounding cells and improve the outcome of gene transfer. To improve the efficiency of vector-mediated gene therapy and to investigate the utility of the intercellular trafficking properties of VP22-linked protein for the treatment for DMD, the recombinant adenoviruses Ad-VP22, Ad-MICDYS, and Ad-VP22-MICDYS were constructed and the VP22-mediated shuttle effect was evaluated both in vitro and in vivo. About 92 +/- 3.6% of cells were microdystrophin positive 48 hr postinfection with Ad-VP22-MICDYS. The number of centralized nuclei in Ad-VP22-MICDYS-transduced tibialis anterior (TA) muscle was significantly reduced, from 78 +/- 5.2 to 20 +/- 2.5%, by 2 weeks postinjection. By 2 months postinjection, the average number of microdystrophin-positive fibers in TA muscle injected with Ad-VP22-MICDYS was 2.2 times more than that of TA muscle injected with Ad-MICDYS. Ad-VP22-MICDYS led to significant recovery of force-producing capabilities in TA muscle. These results demonstrate that VP22 greatly augmented adenovirus-mediated microdystrophin delivery to C2C12 cells and to the skeletal muscles of dystrophin-deficient (mdx) mice. These results highlight the efficiency of VP22-mediated intercellular protein delivery for the potential therapy of DMD and suggest that VP22 may be a promising tool with which to enhance the efficacy of adenoviral gene transfer for somatic gene therapy of DMD.
Xiong
Fu
F
Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
Xiao
Shaobo
S
Peng
Funing
F
Zheng
Hui
H
Yu
Meijuan
M
Ruan
Yechun
Y
Li
Wanyi
W
Shang
Yanchang
Y
Zhao
Cuiping
C
Zhou
Wenliang
W
Chen
Huanchun
H
Chamberlain
Jeffrey S
JS
Fang
Liurong
L
Zhang
Cheng
C
D000256:Adenoviridae / Q000235:genetics*; D000257:Adenoviridae Infections / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D016189:Dystrophin / Q000235:genetics* / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*
D016189:Dystrophin; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22