Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency

Preclinical & Phase I/II Trials of AAV-AAT Vectors: Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV2-CB-hAAT) Gene Vector to AAT-Deficient Adults

National Heart, Lung, and Blood Institute (NHLBI), Alpha-1 Foundation, University of Florida, National Center for Research Resources (NCRR)

Individuals with a deficiency of the Alpha 1-antitrypsin (AAT) protein are at risk for developing emphysema and liver damage. Researchers have developed a way to introduce normal AAT genes into muscle cells so that the AAT protein is produced at normal levels. This study will evaluate the safety of the experimental gene transfer procedure in individuals with AAT deficiency.

AAT deficiency is a genetic disorder in which individuals have inadequate levels of the AAT protein. AAT protects the lungs from white blood cell enzymes that can damage air sacs within the lungs, potentially leading to emphysema. Experimental gene transfer procedures, in which normal copies of genes are inserted into cells, are being developed to treat many genetic diseases, including AAT deficiency. In this study, a modified virus, adeno-associated virus (AAV), has been genetically engineered to contain a normal copy of the AAT gene. When AAV is combined with the AAT gene, the resulting agent, rAAV2-CB-hAAT, is able to carry normal copies of the AAT gene into muscle cells to produce additional AAT. The purpose of this study is to evaluate the safety of injecting rAAV2-CB-hAAT into individuals with AAT deficiency. This 13-month study will enroll individuals with AAT deficiency. Participants currently using AAT protein replacement will discontinue its use for 15 weeks during the study. Participants will first attend a baseline study visit, which will include a medical history review; a physical examination; an electrocardiogram (ECG) to record heart activity; blood, urine, and semen collection; pulmonary function tests; and chest and arm scans. Participants will then attend a 5-day inpatient visit, during which they will receive a series of injections consisting of one of four different doses of rAAV2-CB-hAAT. Physical examinations will occur on all 5 inpatient days; pulmonary function testing, arm circumference measurements, and collection of blood, urine, and semen will occur on selected days of the inpatient stay. Follow-up study visits, with possible overnight stays, will occur on Days 14 and 90. On Days 30, 45, 60, 75, 180, 270, and 365, participants will have blood drawn at a local clinic. On these same days, study staff will contact participants by telephone to review their medical history and symptoms. Unused blood and semen samples will be frozen and stored for future research purposes. Participants will have yearly follow-up evaluations by either telephone or mail for a total of 15 years.

Participants will attend a 5-day inpatient visit, during which they will receive a series of injections consisting of one of four different doses of rAAV2-CB-hAAT.

Inclusion Criteria: Diagnosed with AAT deficiency Forced expiratory volume in one second (FEV1) greater than 24% of predicted value (post bronchodilator) Willing to discontinue AAT protein replacement 4 weeks prior to study entry, and to resume 11 weeks after rAAV2-CB-hAAT has been administered Willing to discontinue aspirin, aspirin-containing products, and other drugs that may alter platelet function 7 days prior to study entry, and to resume 24 hours after rAAV2-CB-hAAT has been administered Willing to use contraception throughout the study Exclusion Criteria: Required antibiotic therapy for a respiratory infection in the 28 days prior to rAAV2-CB-hAAT administration Required oral or systemic corticosteroids in the 28 days prior to rAAV2-CB-hAAT administration Liver disease Currently receiving or has received an investigational study agent in the 30 days prior to study entry Received gene transfer agents in the 6 months prior to study entry Currently smokes cigarettes or uses illegal drugs History of immune response to human AAT replacement History of platelet dysfunction Any other medical condition that the investigator deems unsuitable for study participation Pregnant or breastfeeding

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