Capsid-modified adenoviral vectors for improved muscle-directed gene therapy

Kilian Guse; Masataka Suzuki; Gautam Sule; Terry K. Bertin; Henna Tyynismaa; Sofia Ahola-Erkkilä; Donna Palmer; Anu Suomalainen; Philip Ng; Vincenzo Cerullo; Akseli Hemminki; Brendan Lee

doi:10.1089/hum.2012.003

Capsid-modified adenoviral vectors for improved muscle-directed gene therapy

Kilian Guse, Masataka Suzuki, Gautam Sule, Terry K. Bertin, Henna Tyynismaa, Sofia Ahola-Erkkilä, Donna Palmer, Anu Suomalainen, Philip Ng, Vincenzo Cerullo, Akseli Hemminki, Brendan Lee

Metabolism and Systems Science

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1065-1070
Number of pages	6
Journal	Human Gene Therapy
Volume	23
Issue number	10
Early online date	26 Jun 2012
DOIs	https://doi.org/10.1089/hum.2012.003
Publication status	Published - Oct 2012

Keywords

Adenoviridae/genetics
Animals
Capsid/metabolism
Gene Expression
Genetic Therapy
Genetic Vectors/genetics
Mice
Mice, Inbred C57BL
Mice, Inbred mdx
Muscle, Skeletal/metabolism
Organ Specificity
Time Factors

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10.1089/hum.2012.003

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title = "Capsid-modified adenoviral vectors for improved muscle-directed gene therapy",

abstract = "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.",

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author = "Kilian Guse and Masataka Suzuki and Gautam Sule and Bertin, {Terry K.} and Henna Tyynismaa and Sofia Ahola-Erkkil{\"a} and Donna Palmer and Anu Suomalainen and Philip Ng and Vincenzo Cerullo and Akseli Hemminki and Brendan Lee",

year = "2012",

month = oct,

doi = "10.1089/hum.2012.003",

language = "English",

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pages = "1065--1070",

journal = "Human Gene Therapy",

issn = "1043-0342",

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T1 - Capsid-modified adenoviral vectors for improved muscle-directed gene therapy

AU - Guse, Kilian

AU - Suzuki, Masataka

AU - Sule, Gautam

AU - Bertin, Terry K.

AU - Tyynismaa, Henna

AU - Ahola-Erkkilä, Sofia

AU - Palmer, Donna

AU - Suomalainen, Anu

AU - Ng, Philip

AU - Cerullo, Vincenzo

AU - Hemminki, Akseli

AU - Lee, Brendan

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - Adenoviridae/genetics

KW - Animals

KW - Capsid/metabolism

KW - Gene Expression

KW - Genetic Therapy

KW - Genetic Vectors/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred mdx

KW - Muscle, Skeletal/metabolism

KW - Organ Specificity

KW - Time Factors

UR - http://europepmc.org/abstract/med/22888960

U2 - 10.1089/hum.2012.003

DO - 10.1089/hum.2012.003

M3 - Article

C2 - 22888960

SN - 1043-0342

VL - 23

SP - 1065

EP - 1070

JO - Human Gene Therapy

JF - Human Gene Therapy

IS - 10

ER -

Capsid-modified adenoviral vectors for improved muscle-directed gene therapy

Abstract

Keywords

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