Gene Therapy for Alpha 1- Antitrypsin Deficiency

Gene Therapy for Alpha 1- Antitrypsin Deficiency

This is a study of gene therapy to treat alpha 1-antitrypsin (AAT) deficiency. This study aims to treat AAT deficiency with a single administration of AAV8hAAT(AVL), a gene therapy that codes for an oxidation resistant form of the AAT protein, which if safe and if efficacious, will protect the lung on a persistent basis. We hope to learn the safety/toxicity and initial evidence of efficacy of intravenous delivery of this gene therapy to alpha 1-antitrypsin deficient individuals.

Inclusion Criteria:

• AAT genotype ZZ, or Z null heterozygotes, and if on augmentation therapy, pre-therapy AAT serum levels <11 μM
• Emphysema as assessed by chest high resolution computational tomography (HRCT)
• Lung function parameters consistent with mild to moderate loss of lung function and the presence of emphysema.
• Troponin T within normal limits
• Normal liver ultrasound and serum alpha fetoprotein
• Normal kidney function
• No contraindications to receiving corticosteroid immunosuppression

Exclusion Criteria:

• Individuals receiving systemic corticosteroids or other immunosuppressive medications for pre-existing conditions.
• Inability to tolerate immunosuppression with corticosteroids (e.g., uncontrolled diabetes)
• Individuals with an immunodeficiency disease, or evidence of active infection of any type, including human immunodeficiency virus
• Evidence of major central nervous system, major psychiatric, musculoskeletal or immune disorder
• Prior history of myocardial infarction or cancer within the past 5 years (other than basal cell carcinoma of the skin)
• Decompensated heart failure (NY4A class III-IV at time of baseline clinical assessment)
• Abnormal ECG at screening with findings consistent with cardiac disease
• Females who are currently pregnant or lactating
• Any history of allergies to drugs used for bronchoscopy, including xylocaine, lidocaine, versed, valium, atropine, pilocarpine, isoproterenol, terbutaline, aminophylline, or any local anesthetic
• Individuals receiving experimental medications or participating in another experimental protocol for at least 3 months prior to entry to the study
• Use of oxygen supplementation
• Risk for thromboembolic disease
• History of significant cardiovascular disease, hypertension, prior myocardial infarction and/or cerebrovascular event
• Individuals who are currently on beta-blockers, or other cardiac therapy related drugs
• Prior history of hypersensitivity or anaphylaxis associated with the administration of any AAT product