Gene therapy using AAV8 to replace defective alpha-1 antitrypsin

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

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.

Why it matters

Who can join: the full rules

Inclusion Criteria:

* AAT genotype ZZ, or Z null heterozygotes, and if on augmentation therapy, pre-therapy AAT serum levels \<11 μM
* Evidence of mild to moderate disease by the following lung function parameters on PFT and/or chest high resolution computational tomography (HRCT)

  * Emphysema as assessed by HRCT and/or
  * Lung function parameters consistent with mild to moderate loss of lung function, in either category 1 or category 2 below:

    1. Mild lung dysfunction: FEV1/FVC \< 0.70 and FEV1 ≥ 80% predicted
    2. Moderate lung dysfunction: FEV1/FVC \< 0.70 and FEV1 40 - \< 80% predicted and DLCO \<80% predicted.
* 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 chronic (used daily for greater than 30 days) systemic corticosteroids or other immunosuppressive medications for pre-existing conditions (inhaled corticosteroids for pulmonary associated issues are permitted)
* 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
* 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 it's running

• 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: Madeline Galbraith
• Email: meg4013@med.cornell.edu
• Phone: 646-962-2672

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Other studies for the same condition or treatment. Recruiting studies are listed first.

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.