Work in the lab involves in-depth research investigating the use of gene therapy for genetic diseases that affect children; including cystic fibrosis, alpha-1 antitrypsin, Type 1 diabetes, and disorders of fatty acid oxidation. The lab also studies the mechanism of AAV persistence to better understand the potential for long-term safe and effective gene therapy; which is evaluated through Phase I clinical trials
Much was learned in the early cystic fibrosis clinical trials, including the paucity of AAV2 receptors on the luminal side of the airways. As a result, the lab recently designed a more robust expression cassette delivering a CFTR “mini gene” and has determined that AAV1 is superior to AAV2 and AAV5 at transducing airways. This new generation of viral vectors for CF is currently undergoing pre-clinical testing in preparation for human testing.
We are developing hybrid rAAV-RNAi approaches to treat AAT deficient liver disease. Given the need to down regulate Z-AAT, the lab has begun examining a number of innovative approaches to long-term expression of therapeutic RNAs using the rAAV platform.
Our lab is also studying the application of rAAV-based transduction of skeletal muscle for those Fatty Acid Oxidation Disorder deficiencies that are most common in humans. Through mouse models we are seeking to determine whether rAAV9 (vs. rAAV1) mediated transduction of skeletal and cardiac muscle will result in the improvement of acyl carnitine profiles and MRS profiles in mice with these disorders. This will lead to formal pre-clinical toxicology studies associated with muscle delivery of the targeted rAAV therapies in anticipation of new phase I clinical trials of gene therapy for these disorders.
Members from the Flotte lab presents five posters at ASGT annual meeting providing updates covering ongoing research.
Lab leader, Dr. Christian Mueller, becomes a 2009 Parker B. Francis Fellow.