Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency

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Brief Title

Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency

Official Title

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

Brief Summary

      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

Detailed Description

      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.

Study Phase

Early Phase 1

Study Type


Primary Outcome

Arm circumference


Alpha 1-Antitrypsin Deficiency


rAAV2-CB-hAAT Gene Vector

Study Arms / Comparison Groups

Description:  rAAV2-CB-hAAT Gene Vector


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

March 2004

Completion Date

January 2020

Primary Completion Date

October 2006

Eligibility Criteria

        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

          -  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

          -  Pregnant or breastfeeding




18 Years - N/A

Accepts Healthy Volunteers



Terence R. Flotte, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

University of Massachusetts, Worcester


 National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Terence R. Flotte, MD, Principal Investigator, UMass Medical School

Verification Date

April 2020