Gene therapy using AAV8 to replace defective alpha-1 antitrypsin
Gene Therapy for Alpha 1- Antitrypsin Deficiency
This trial will try a one-time IV gene therapy (AAV8hAAT(AVL)) to produce an oxidation-resistant AAT protein in adults with ZZ or Z/null alpha-1 antitrypsin deficiency who have emphysema.
Quick facts
| Phase | Phase 1 |
|---|---|
| Study type | Interventional |
| Enrollment | 16 (estimated) |
| Ages | 18 Years to 70 Years |
| Sex | All |
| Sponsor | Weill Medical College of Cornell University Academic / other |
| Locations | 1 site (New York, New York) |
| Trial ID | NCT06996756 on ClinicalTrials.gov |
What this trial studies
This is a Phase 1, single-administration, open-label gene therapy program using an AAV8 vector encoding an oxidation-resistant form of alpha-1 antitrypsin (AAV8hAAT(AVL)) delivered intravenously. The primary goal is to measure safety and toxicity, with secondary aims to look for initial signs that the expressed protein can persist and protect the lung. Eligible participants have ZZ or Z/null genotypes, imaging-confirmed emphysema, and lung function consistent with mild-to-moderate disease, and must be able to tolerate short-term corticosteroid immunosuppression. Participants will undergo screening labs and imaging, receive a single IV dose at the research center, and be followed closely with laboratory and pulmonary assessments.
Who should consider this trial
Good fit: Adults with ZZ or Z/null genotypes who have CT-confirmed emphysema, mild-to-moderate loss of lung function, normal cardiac/liver/kidney tests, and who can tolerate short-term corticosteroid immunosuppression are the ideal candidates.
Not a fit: People with active infections, immunodeficiency, inability to tolerate immunosuppression, major uncontrolled comorbidities (including significant liver disease or prior myocardial disease), or those on chronic systemic immunosuppression are unlikely to benefit or be eligible.
Why it matters
Potential benefit: If successful, a single IV dose could provide long-lasting production of a stable AAT protein and reduce lung damage and the need for repeated augmentation infusions.
How similar studies have performed: AAV-based liver-directed gene therapies have shown promise in animal models and in early human work for other genetic diseases, but durable human data specifically replacing AAT remain limited.
Eligibility criteria
Show full inclusion / exclusion 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
Where this trial is running
New York, New York
- WCMC Department of Genetic Medicine — New York, New York, United States (Recruiting)
Study contacts
- Principal investigator: Ronald G Crystal, MD — Weill Medical College of Cornell University
- Study coordinator: Niamh Savage
- Email: nis2049@med.cornell.edu
- Phone: 646-962-5527
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.