Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle.

Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Research Abstract Details 

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Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Abstract Text:

Maja Z Salva,Charis L Himeda,Phillip Wl Tai,Eiko Nishiuchi,Paul Gregorevic,James M Allen,Eric E Finn,Quynh G Nguyen,Michael J Blankinship,Leonard Meuse,Jeffrey S Chamberlain,Stephen D Hauschka,

Systemic delivery of recombinant adeno-associated virus (rAAV) 6 vectors mediates efficient transduction of the entire striated musculature, making this an attractive strategy for muscle gene therapy. However, owing to widespread transduction of non-muscle tissues, optimization of this method would benefit from the use of muscle-specific promoters. Most such promoters either lack high-level expression in certain muscle types or are too large for inclusion in rAAV vectors encoding microdystrophin. Here, we describe novel regulatory cassettes based on enhancer/promoter regions of murine muscle creatine kinase (CK) and alpha-myosin heavy-chain genes. The strongest cassette, MHCK7 (770 bp), directs high-level expression comparable to cytomegalovirus and Rous sarcoma virus promoters in fast and slow skeletal and cardiac muscle, and low expression in the liver, lung, and spleen following systemic rAAV6 delivery in mice. Compared with CK6, our previous best cassette, MHCK7 activity is approximately 400-, approximately 50-, and approximately 10-fold higher in cardiac, diaphragm, and soleus muscles, respectively. MHCK7 also directs strong microdystrophin expression in mdx muscles. While further study of immune responses to MHCK7-regulated microdystrophin expression is needed, this cassette is not active in dendritic cell lines. MHCK7 is thus a highly improved regulatory cassette for experimental studies of rAAV-mediated transduction of striated muscle.

Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Publishing Authors By Initials

MZ Salva,CL Himeda,PW Tai,E Nishiuchi,P Gregorevic,JM Allen,EE Finn,QG Nguyen,MJ Blankinship,L Meuse,JS Chamberlain,SD Hauschka,

For similar macromolecular substances: polymers: biopolymers: microfilament proteins: myosins: myosin type ii: cardiac myosins: ventricular myosins research abstracts see: macromolecular substances: polymers: biopolymers: microfilament proteins: myosins: myosin type ii: cardiac myosins: ventricular myosins research

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Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular therapy : the journal of the American So

VOLUME: 15

Page Numbers: 320-9

Journal Abbreviation: Mol. Ther.

ISSN: 1525-0016

DAY: 3

MONTH: Feb

YEAR: 2007

Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Information

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LANGUAGE: eng

NlmUniqueID: 100890581

Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Keywords Mesh Terms:

KEYWORDS: Ventricular Myosins

MESH TERMS: metabolism

Chemical & Substance for Abstract: Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Information

Substance Name: Ventricular Myosins

Registry Number: EC 3.6.1.-

Grant and Affiliation Information for Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle.

AFFILIATION: Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R24 HL64387

ACRONYM: HL

MEDLINETA: Mol Ther

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