Clinical trial NCT06996756: Gene Therapy for Alpha-1 Antitrypsin Deficiency
Official title: Gene Therapy for Alpha-1 Antitrypsin Deficiency
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Alpha 1-Antitrypsin Deficiency
Keywords: AAT
Emphysema
Gene therapy
DLCO
Augmentation therapy
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2025-05-30
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a study of gene therapy to treat alpha-1 antitrypsin 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 (AAT) deficient individuals.


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

Primary outcomes:
measure: Safety of AAV8hAAT(AVL), as measured by number of subjects with at least 1 serious adverse event.
timeFrame: Approximately 1 year
measure: Toxicity of AAV8AAT(AVL), as measure by number of subjects with any dose limiting toxicity
timeFrame: Approximately 2 years
measure: Establishing a maximum tolerable dose of AAV8hAAT(AVL)
timeFrame: Approximately 2 years
Secondary outcomes:
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 4 weeks
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 3 months
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 6 months
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 12 months
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 2 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 3 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 4 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum
timeFrame: 5 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid
timeFrame: 12 months
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid
timeFrame: 2 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid
timeFrame: 3 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid
timeFrame: 4 years
measure: Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid
timeFrame: 5 years
Other outcomes:
Locations:
city: New York
country: United States
facility: WCMC Department of Genetic Medicine
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Ronald G Crystal, MD
role: PRINCIPAL_INVESTIGATOR
References: