Gene Therapy for Alpha-1 Antitrypsin Deficiency

Weill Cornell Medicine (WCM)

Status and phase: Not yet enrolling; Phase 1

Conditions: Alpha 1-Antitrypsin Deficiency

Treatments: Biological: AAV8hAAT(AVL)

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06996756

24-06027591

1R61HL169190 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Enrollment: 16 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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16 participants in 4 patient groups

AAV8hAAT(AVL) - 5x10¹¹ gc/kg

Experimental group

Description:

Lowest dose of vector genome copies per kilogram

Treatment:

Biological: AAV8hAAT(AVL)

AAV8hAAT(AVL) - 2x10¹² gc/kg

Experimental group

Treatment:

Biological: AAV8hAAT(AVL)

AAV8hAAT(AVL) - 5x10¹² gc/kg

Experimental group

Treatment:

Biological: AAV8hAAT(AVL)

AAV8hAAT(AVL) - 2x10¹³ gc/kg

Experimental group

Description:

Highest dose of vector genome copies per kilogram

Treatment:

Biological: AAV8hAAT(AVL)