This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A recombinant virus vector was constructed from adeno associated virus-AAV that has been altered to carry the human alpha 1-antitrypsin-hAAT gene expressed from a hybrid chicken beta actin promoter with a cytomegalovirus enhancer. This construct has been shown to express hAAT in animal models closely matching the proposed human trial. Our group is currently performing a phase I safety and dose-finding study of a recombinant adeno-associated virus serotype 2-rAAV2-AAT vector given by intramuscular-IM administration to Alpha 1-Antitrypsin Deficient-AATD patients. Mouse data suggests that this same rAAV-AAT gene cassette will produce much higher serum levels of AAT if it is packaged in an AAV serotype 1 pseudotyped capsid. This proposed clinical trial is an open label, phase I study administering rAAV1-CB-hAAT gene vector intramuscularly to AAT deficient human subjects who meet entry criteria. It will cover the same dose range as the current rAAV2-AAT study- approximately 2x1012 to 6.9x1013 vector genomes per patient. Safety parameters will be measurement of changes, in serum chemistries and hematology, urinalysis, pulmonary function testing, semen assay for vector genomes, immunologic response to AAT and AAV, as well as reported subject history of any symptoms.
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