We are developing an improved adeno-associated virus (AAV)-based gene therapy vector
that we call “enhanced AAV” or “eAAV” for short. eAAV is specifically designed for gene
delivery to skeletal muscle tissue. Based on preliminary studies in mice we expect it will be
approximately 100 times more effective than the recombinant AAVs (rAAV1 and rAAV8) used in
recent clinical trials. This gain in efficiency should allow us to achieve far higher levels of
therapeutic transgene products, either directly, due to increased transduction efficiency, or
indirectly, by allowing us to use less vector and thereby reduce the likelihood of host immune
responses to the transgene product.
The aims of this grant are threefold. Aim 1 is to finalize the design of the eAAV product in
cell culture and rodent studies. Aim 2 is to test the final eAAV product in nonhuman primates,
and Aim 3 is to determine whether or not it poses any unique safety risks compared to other
rAAV vectors. Aim 2 comprises the bulk of the project. Here we will compare eAAV to rAAV for
its ability to express both alpha-1 antitrypsin (AAT) and the human immunodeficiency virus
(HIV)-inhibitor eCD4 from skeletal muscle. Achieving therapeutic levels of AAT would allow for
a permanent cure of genetic AAT-deficiency while achieving reliably high levels of eCD4
expression would enable a one-shot, potentially life-long treatment for HIV.