Gene Therapy for Alpha 1- Antitrypsin Deficiency

Overview

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.

Interventions

• Biological AAV8hAAT(AVL)
  AAV8hAAT(AVL) gene transfer vector

Primary outcome measures

• Safety of AAV8hAAT(AVL), as measured by number of subjects with at least 1 serious adverse event. [Time frame: Approximately 1 year]
• Toxicity of AAV8AAT(AVL), as measure by number of subjects with any dose limiting toxicity [Time frame: Approximately 2 years]
• Establishing a maximum tolerable dose of AAV8hAAT(AVL) [Time frame: Approximately 2 years]

Secondary outcome measures (12)

• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 4 weeks]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 3 months]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 6 months]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 12 months]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 2 years]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 3 years]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 4 years]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum [Time frame: 5 years]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid [Time frame: 12 months]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid [Time frame: 2 years]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid [Time frame: 3 years]
• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid [Time frame: 4 years]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• WCMC Department of Genetic Medicine — New York

Identifiers

NCT: NCT06996756 · 24-06027591 · 1R61HL169190

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗