Gene Therapy for Alpha 1- Antitrypsin Deficiency

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.

Study Overview

• Status: Recruiting
• Conditions: Alpha 1-Antitrypsin Deficiency
• Intervention / Treatment: Biological: AAV8hAAT(AVL)

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sandra Hyde; Phone Number: 646-962-2672; Email: sah2003@med.cornell.edu
• Study Contact Backup: Name: Niamh Savage; Phone Number: 646-962-5527; Email: nis2049@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • WCMC Department of Genetic Medicine
      • Contact: Sandra Hyde; Phone Number: 646-962-2672; Email: sah2003@med.cornell.edu
      • Principal Investigator: Ronald Crystal, MD
      • Contact: Niamh Savage; Phone Number: 646-962-5527; Email: nis2049@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AAV8hAAT(AVL) - 5x10¹¹ gc/kg; Lowest dose of vector genome copies per kilogram	Biological: AAV8hAAT(AVL); AAV8hAAT(AVL) gene transfer vector
Experimental: AAV8hAAT(AVL) - 2x10¹² gc/kg	Biological: AAV8hAAT(AVL); AAV8hAAT(AVL) gene transfer vector
Experimental: AAV8hAAT(AVL) - 5x10¹² gc/kg	Biological: AAV8hAAT(AVL); AAV8hAAT(AVL) gene transfer vector
Experimental: AAV8hAAT(AVL) - 2x10¹³ gc/kg; Highest dose of vector genome copies per kilogram	Biological: AAV8hAAT(AVL); AAV8hAAT(AVL) gene transfer vector

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of AAV8hAAT(AVL), as measured by number of subjects with at least 1 serious adverse event.	Serious adverse events will only be included if assessed as related to the gene therapy.	Approximately 1 year
Toxicity of AAV8AAT(AVL), as measure by number of subjects with any dose limiting toxicity	If none of the first 4 dosed participants experiences a DLT by the end of Day 28 after treatment (Day 1), the dose of AAV8hAAT(AVL) will be escalated, and the next cohort of participants will start treatment at the next-higher dose level.	Approximately 2 years
Establishing a maximum tolerable dose of AAV8hAAT(AVL)	If none of the first 4 participants treated at the highest dose level experiences a DLT by the end of Day 28 after treatment, this dose will be determined to be the maximum administered dose (MAD)	Approximately 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	4 weeks
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	3 months
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	6 months
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	12 months
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	2 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	3 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	4 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum	Serum levels of AAT will be measured in the blood	5 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid	Levels of AAT in the lung will be measured by bronchoscopy (if performed)	12 months
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid	Levels of AAT in the lung will be measured by bronchoscopy (if performed)	2 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid	Levels of AAT in the lung will be measured by bronchoscopy (if performed)	3 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid	Levels of AAT in the lung will be measured by bronchoscopy (if performed)	4 years
Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid	Levels of AAT in the lung will be measured by bronchoscopy (if performed)	5 years

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Ronald G Crystal, MD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2025
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): August 1, 2032

Study Registration Dates

• First Submitted: May 21, 2025
• First Submitted That Met QC Criteria: May 21, 2025
• First Posted (Actual): May 30, 2025

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Gene therapy; Emphysema; DLCO; AAT; Augmentation therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Liver Diseases; Subcutaneous Emphysema; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Emphysema; alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: 24-06027591; 1R61HL169190 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: As the proposed experiments become published in scientific journals, the cleaned, item-level spreadsheet data for all variables will also be shared openly, along with example quantifications and transformations from initial raw data. Final files used to generate specific analyses to answer the Specific Aims and related results will also be shared. The rationale for sharing only cleaned data is to foster ease of data reuse. If any data collection arising from the proposed studies are not shared by publication within one year after the proposed award period ends, the unpublished data will be similarly shared in public domains for ease of access.
• IPD Sharing Time Frame: At the time of publication, and after final analyses have been completed.
• IPD Sharing Access Criteria: Access to the data may require Material Transfer Agreements, Non-Disclosure Agreements, or other limitations on licensing access and will be managed by the PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No