Introduction

Many muscle proteins are encoded by large genes. Mutations in these genes have been associated with various forms of myopathy afflicting the skeletal muscle and/ or the heart (Table 12.1). Currently, there is no cure for these devastating muscle diseases. Replacing the defective gene with a functional gene offers the hope for correcting inherited muscle diseases at the DNA level. The challenge lies in delivering these large therapeutic genes to the affected muscles throughout the body. Due to their excellent transduction efficiency, viral vectors are often the top choice for in vivo gene delivery. Among different viral vectors, adeno-associated virus (AAV) is particularly attractive for muscle gene therapy. AAV is the only vector capable of whole-body muscle transduction alter single intravascular injection (Bostick et al. 2007;

Department of Molecular Microbiology and Immunology, One Hospital Dr, Columbia,

MO, 65212, USA

e-mail: [email protected]

DOI 10.1007/978-1-4419-1207-7_12, © Springer Science+Business Media, LLC 2010

Table 12.1. Examples of large genes invovled in muscle diseases

Gene size Gene name Coding sequence Protein size Disease

Table 12.1. Examples of large genes invovled in muscle diseases

Gene size Gene name Coding sequence Protein size Disease

6 mb

Titin

82 kb

4,2GG kD

Dilated cardiomyopathy 1G T Tibial distal myopathy Limb-girdle muscular dystrophy 2J Hypertrophic myopathy Hereditary myopathy with early respiratory failure

2.3 mb

Dystrophin

ll.l kb*

42l kD

Duchenne muscular dystrophy Becker muscular dystrophy X-linked dilated cardiomyopathy

26G kb

a-2 Laminin (merosin)

1G kb

342 kD

Congenital muscular dystrophy

15G kb

Dysferlin

6.2 kb

23l kD

Limb-girdle muscular dystrophy 2B Miyoshi myopathy Anterior tibial distal myopathy

22.9 kb

Myosin heavy chain 7

5.8 kb

212 kD

Familial hypertrophic cardiomyopathy 1 Dilated cardiomyopathy 1S Midventricular hypertrophic cardiomyopathy Myosin storage myopathy Laing distal myopathy

* Highly abbreviated mini- and micro-genes are currently being developed for dystrophin-deficient muscle diseases.

* Highly abbreviated mini- and micro-genes are currently being developed for dystrophin-deficient muscle diseases.

Gregorevic et al. 2004; Wang et al. 2005; Yue et al. 2008). For this reason, there has been a great interest in developing AAV-mediated gene therapy for muscle diseases. In this chapter, we will review different strategies used to deliver large therapeutic genes with AAV vectors. We will also discuss vectors based on other large DNA viruses, including adenovirus and herpes simplex virus.

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