Despite many successful examples of gene transfer to limited areas of postnatal skeletal muscle, regional or systemic delivery suitable to treat inherited muscle diseases such as Duchenne muscular dystrophy (DMD) has proved elusive. Gene or cell transfer during the fetal stage holds the potential of more efficient and widespread genetic complementation of dystrophin deficiency in DMD. An important rationale to pursue therapeutic strategies for the dystrophic fetus is that muscle stem cells are more plentiful in fetal muscle than in adult muscle. Furthermore, viral vector-mediated gene delivery and engraftment of genetically engineered muscle precursor cells to skeletal muscle may be enhanced during this fetal stage. Therefore, we will explore the feasibility of performing gene and cell transfer to muscle in utero exploiting the benefits of lower tissue mass and immune immaturity of the fetus as well as the earlier stage of muscle development. ? Specific Aims: ? 1. To evaluate in utero dystrophin gene delivery using high-capacity adenoviral (HC-Ad) vectors. ? 2. To evaluate in utero dystrophin gene delivery using adeno-associated viral (AAV) vectors. ? 3. To evaluate in utero gene delivery using early progenitor myogenic cells ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050565-05
Application #
7455006
Study Section
Special Emphasis Panel (ZRG1-GRM (04))
Program Officer
Nuckolls, Glen H
Project Start
2004-09-15
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$219,858
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cai, Lingzhi; Koppanati, Bhanu Munil; Bertoni, Carmen et al. (2014) In utero delivery of oligodeoxynucleotides for gene correction. Methods Mol Biol 1114:399-411
Koppanati, B M; Li, J; Reay, D P et al. (2010) Improvement of the mdx mouse dystrophic phenotype by systemic in utero AAV8 delivery of a minidystrophin gene. Gene Ther 17:1355-62
Koppanati, B M; Li, J; Xiao, X et al. (2009) Systemic delivery of AAV8 in utero results in gene expression in diaphragm and limb muscle: treatment implications for muscle disorders. Gene Ther 16:1130-7
Bilbao, Roberto; Reay, Daniel P; Li, Juan et al. (2005) Patterns of gene expression from in utero delivery of adenoviral-associated vector serotype 1. Hum Gene Ther 16:678-84