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Adenoviral vectors for treatment of ...

Hartigan-O'Connor, Dennis Joseph.

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Adenoviral vectors for treatment of Duchenne muscular dystrophy.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Adenoviral vectors for treatment of Duchenne muscular dystrophy./
Author:	Hartigan-O'Connor, Dennis Joseph.
Description:	158 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0535.
Contained By:	Dissertation Abstracts International64-02B.
Subject:	Biology, Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3079456

Adenoviral vectors for treatment of Duchenne muscular dystrophy.
Hartigan-O'Connor, Dennis Joseph.

Adenoviral vectors for treatment of Duchenne muscular dystrophy. - 158 p.

Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0535.

Thesis (Ph.D.)--University of Michigan, 2003.

First-generation adenovirus (Ad) vectors are unsuitable for gene replacement therapy, due to immune responses and low cloning capacity. These problems may be exacerbated in the inflammatory milieu of dystrophic muscle. It is hoped that gutted Ad vectors, which do not carry viral genes, may provide effective gene transfer without eliciting acute toxicity or a longer-term, antigen-specific anti-adenovirus response. Unfortunately, gutted Ad vectors share some drawbacks with conventional Ad vectors and present new challenges. First, gutted vectors share the tropism of conventional adenovirus and could elicit an anti-transgene response in patients with null alleles. Second, clinical grade production of gutted Ad vectors has not been achieved.Subjects--Topical Terms:

1017734
Biology, Microbiology.

Adenoviral vectors for treatment of Duchenne muscular dystrophy.
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008 130614s2003 eng d
035 $a (UnM)AAI3079456
035 $a AAI3079456
040 $a UnM $c UnM
100 1 $a Hartigan-O'Connor, Dennis Joseph. $3 1949436
245 1 0 $a Adenoviral vectors for treatment of Duchenne muscular dystrophy.
300 $a 158 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0535.
500 $a Chair: Jeffrey S. Chamberlain.
502 $a Thesis (Ph.D.)--University of Michigan, 2003.
520 $a First-generation adenovirus (Ad) vectors are unsuitable for gene replacement therapy, due to immune responses and low cloning capacity. These problems may be exacerbated in the inflammatory milieu of dystrophic muscle. It is hoped that gutted Ad vectors, which do not carry viral genes, may provide effective gene transfer without eliciting acute toxicity or a longer-term, antigen-specific anti-adenovirus response. Unfortunately, gutted Ad vectors share some drawbacks with conventional Ad vectors and present new challenges. First, gutted vectors share the tropism of conventional adenovirus and could elicit an anti-transgene response in patients with null alleles. Second, clinical grade production of gutted Ad vectors has not been achieved.
520 $a The goal of this thesis is to determine whether these two problems with gutted adenovirus, low virus yield and immune response to transgene products, can be overcome. Two hypotheses were tested: (1) poor growth of gutted adenovirus vectors in tissue culture is caused primarily by failure of sub-optimal replication origins to compete for replication factors; and (2) in healthy muscle tissue, but not necessarily in dystrophic tissue, the immune response to transgene products delivered by a vector with promiscuous tropism can be eliminated by strict tissue-specific gene expression.
520 $a We explored whether gutted virus production would be facilitated by transfection into cells expressing replication factors or by use of synthetic terminal protein-DNA complex. Both methods were effective, together yielding a 1000-fold increase in gutted virus titer.
520 $a Muscle tissue from the mdx mouse, a model for Duchenne muscular dystrophy (DMD), is characterized by infiltrating antigen-presenting cells (APCs). We found that mdx mouse muscles mounted a stronger immune response to antigens that can be directly presented by those APCs. However, we did not detect an immune response to beta-galactosidase expressed specifically in muscle by an Ad vector, even at high expression levels. This suggests that cross-presentation is not dramatically more effective in mdx mouse muscle, and that targeted vectors and tissue-specific promoters may be useful tools for evasion of the immune response in dystrophic muscle.
520 $a The results of our studies indicate that gutted vectors carrying muscle-specific transgenes have great potential for gene therapy of DMD.
590 $a School code: 0127.
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Biology, Cell. $3 1017686
650 4 $a Health Sciences, Immunology. $3 1017716
690 $a 0410
690 $a 0307
690 $a 0379
690 $a 0982
710 2 0 $a University of Michigan. $3 777416
773 0 $t Dissertation Abstracts International $g 64-02B.
790 1 0 $a Chamberlain, Jeffrey S., $e advisor
790 $a 0127
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3079456