Several groups have demonstrated that recombinant adeno-associated virus (rAAV) vectors are capable of sustained expression of therapeutic proteins when administered to skeletal muscle (63). In the case of alpha-1- antitrypsin (AAT) deficiency, a single injection of an AAV vector resulted in sustained AAT secretion at levels that would be therapeutic for humans suffering from this disorder (11microM, approximately 800 microg/ml or 80 mg/dl)(96). There is currently no generally available definitive therapy for these patients, since the one licensed protein replacement product is in short supply and requires weekly intravenous infusions. The goals of this application are (1) to complete preclinical testing of AAV vectors in muscle and to initiate phase I clinical trials of rAAV-AAT gene therapy in patients with AAT deficiency and (2) to determine whether the use of alternative capsids, such as those from different serotypes, can be used to safely enhance vector delivery. The ultimate goal will be to determine the safety and biological efficacy of using gene therapy to augment serum and lung levels of AAT in deficient patients. These goals will be accomplished within 4 specific aims:
Aim (1) To determine the safety and biological activity of rAAV2- AAT in phase I trials of skeletal muscle administration in AAT-deficient patients;
Aim (2) To complete preclinical evaluation of the safety of intramuscular rAAV-AAT vector administration packaged in different serotype capsids in C57B1/6 mice;
Aim (3) To determine whether the efficiency of rAAV delivery to skeletal muscle can be further improved by retargeting capsid tropism to other receptors using a capsid mutagenesis approach to insert new peptide ligands for receptors present in high abundance on skeletal myofibers;
and Aim (4) To further define the potential risks associated with integration and episomal persistence of rAAV in skeletal muscle in the context of a prospective longterm carcinogenesis study. It is anticipated that these translational studies will result in the emergence of one or more new candidate therapies for this disorder.
Showing the most recent 10 out of 30 publications
