Capsid-modified adenoviral vectors for improved muscle-directed gene therapy.
Skeletal muscle represents an attractive target tissue for adenoviral gene therapy to treat muscle disorders and as a production platform for systemic expression of therapeutic proteins. However, adenovirus serotype 5 vectors do not efficiently transduce adult muscle tissue. Here we evaluated whether capsid modifications on adenoviral vectors could improve transduction in mature murine muscle tissue. First-generation and helper-dependent serotype 5 adenoviral vectors featuring the serotype 3 knob (5/3) showed significantly increased transduction of skeletal muscle after intramuscular injection in adult mice. Furthermore, we showed that full-length dystrophin could be more efficiently transferred to muscles of mdx mice using a 5/3-modified helper-dependent adenoviral vector. In contrast to first-generation vectors, helper-dependent adenoviral vectors mediated stable marker gene expression for at least 1 year after intramuscular injection. In conclusion, 5/3 capsid-modified helper-dependent adenoviral vectors show enhanced transduction in adult murine muscle tissue and mediate long-term gene expression, suggesting the suitability of these vectors for muscle-directed gene therapy.
Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Kilian
K
Guse
Masataka
M
Suzuki
Gautam
G
Sule
Terry K
TK
Bertin
Henna
H
Tyynismaa
Sofia
S
Ahola-Erkkilä
Donna
D
Palmer
Anu
A
Suomalainen
Philip
P
Ng
Vincenzo
V
Cerullo
Akseli
A
Hemminki
Brendan
B
Lee
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002213:Capsid / Q000378:metabolism*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D009928:Organ Specificity; D013997:Time Factors