Alpha-1 antitrypsin deficiency is an inherited, genetic condition characterized by reduced serum levels of alpha-1 antitrypsin (AAT) and increased risk of developing emphysema and liver disease, which affects up to 100,000 individuals in the United States. The only currently approved therapy for this orphan disease is weekly intravenous infusions of AAT protein that has been purified from normal plasma donors. The current therapy is in short supply, resulting in low physician motivation to accurately diagnose the vast majority of patients, since not all of the minority of patients who are currently diagnosed are able to receive treatment. The long-term objective of the research proposed in this application is to develop and bring to market a novel, gene therapy product for the treatment of alpha-1 antitrypsin deficiency, using a recombinant adeno-associated virus (rAAV) serotype 1 vector expressing the human AAT gene (rAAV1-CB-hAAT). rAAV vectors are uniquely suitable for in vivo gene therapy because they are non-toxic, highly efficient at transducing a wide variety of non-dividing cell types, and persist for long periods, primarily in episomal form, resulting in long-term expression of the transgene.
The specific aim of this research proposal is to perform a Phase 2 clinical trial of rAAV1-CB-hAAT. The study is a non-randomized, open-label, multi-center, sequential, three-arm, Phase 2 clinical trial evaluating the safety and efficacy of administration of a rAAV1-CB-hAAT vector administered by intramuscular (IM) injection. Each participant will receive rAAV1-CB-hAAT on a single occasion. Three groups of three subjects each will receive rAAV1-CB-hAAT at dosage levels of 6 x 1011 vector genome (vg)/kg, 1.9 x 1012 vg/kg or 6 x 1012 vg/kg by IM injection. Subjects in group 1 will receive a total of 10 IM injections distributed across a single muscle site, subjects in group 2 will receive a total of 32 IM injections distributed across three muscle sites, and subjects in group 3 will receive 100 IM injections distributed across10 muscle sites. Each injection will be given in a volume of 1.35 mL, at the appropriate vector concentration to achieve the desired total vector dose, and the injection density at each administration site (nine IM injections per 4 cm2 skin surface area) will be the same as the injection density that was well tolerated in a previous Phase 1 clinical trial with rAAV1-CB-hAAT. Safety will be monitored by evaluation of adverse events, hematology and clinical chemistry parameters, histological examination of muscle biopsies, and measurement of serum antibodies to AAT. Efficacy will be measured by evaluation of serum concentrations of M-specific AAT and total AAT and serum AAT phenotype determined on isoelectric focusing gels. Additional information to be collected will include presence of the vector in blood or semen, changes in serum anti-AAV antibody titers, and changes in T cell responses to AAV and AAT. Results from this Phase 2 trial will be used to develop a Phase 3 study designed to satisfy the requirements for licensure of a gene therapy treatment for this orphan disease.

Public Health Relevance

Alpha-1 antitrypsin deficiency is an important public health issue that affects up to 100,000 Americans, but the vast majority of patients are not treated due to extremely limited supplies of the only therapy currently available. This project will evaluate a novel, gene therapy product for the treatment of alpha-1 antitrypsin deficiency in a Phase 2 clinical trial to evaluate safety and the ability to achieve serum levels of alpha-1 antitrypsin protein that are adequate to reduce the risk of lung disease caused by alpha-1 antitrypsin deficiency.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Applied Genetic Technologies Corporation
United States
Zip Code
Mueller, Christian; Gernoux, Gwladys; Gruntman, Alisha M et al. (2017) 5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency. Mol Ther 25:1387-1394
Calcedo, Roberto; Somanathan, Suryanarayan; Qin, Qiuyue et al. (2017) Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for ?-1-antitrypsin deficiency. Proc Natl Acad Sci U S A 114:1655-1659
Mueller, Christian; Chulay, Jeffrey D; Trapnell, Bruce C et al. (2013) Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest 123:5310-8
Flotte, Terence R; Trapnell, Bruce C; Humphries, Margaret et al. (2011) Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing ?1-antitrypsin: interim results. Hum Gene Ther 22:1239-47