CTLA4Ig delivered by high-capacity adenoviral vector induces stable expression of dystrophin in mdx mouse muscle.
Adenoviral (Ad) vector-mediated gene delivery of normal, full-length dystrophin to skeletal muscle provides a promising strategy for the treatment of Duchenne muscular dystrophy (DMD), an X-linked recessive, dystrophin-deficient muscle disease. Studies in animal models suggest that successful DMD gene therapy by Ad vector-mediated gene transfer would be precluded by cellular and humoral immune responses induced by vector capsid and transgene proteins. To address the immunity induced by Ad vector-mediated dystrophin gene delivery to dystrophic muscle, we developed high-capacity adenoviral (HC-Ad) vectors expressing mouse dystrophin driven by the muscle creatine kinase promoter (AdmDys) and mCTLA4Ig (AdmCTLA4Ig) individually, or together from one vector (AdmCTLA4Ig/mDys). We found stable expression of dystrophin protein in the tibialis anterior muscles of mdx mice, coinjected with AdmCTLA4Ig and AdmDys, or injected alone with AdmCTLA4Ig/mDys, whereas the expression of dystrophin protein in the control group coinjected with AdmDys and an empty vector decreased by at least 50% between 2 and 8 weeks after administration. Additionally, we observed reductions in Ad vector-induced Th1 and Th2 cytokines, Ad vector-specific cytotoxic T lymphocyte activation and neutralizing anti-Ad antibodies in both experimental groups that received a mCTLA4Ig-expressing vector as compared to the control group. This study demonstrates that the coexpression of mCTLA4Ig and dystrophin in skeletal muscle provided by HC-Ad vector-mediated gene transfer can provide stable expression of dystrophin in immunocompetent, adult mdx mouse muscle and applies a potentially powerful strategy to overcome adaptive immunity induced by Ad vector-mediated dystrophin gene delivery toward the ultimate goal of treatment for DMD.
Department of Neurology, School of Medicine, University of Pittsburgh, PA 15213, USA.
Z
Z
Jiang
G
G
Schiedner
S C
SC
Gilchrist
S
S
Kochanek
P R
PR
Clemens
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000276:immunology; D018796:Immunoconjugates / Q000097:blood / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods*
D000914:Antibodies, Viral; D016207:Cytokines; D016189:Dystrophin; D018796:Immunoconjugates; D000069594:Abatacept