Gene Therapy for Alpha 1- Antitrypsin Deficiency

NCT06996756 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 24-060275911R61HL169190
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alpha 1-Antitrypsin Deficiency

Keywords

AAT; Emphysema; Gene therapy; DLCO; Augmentation therapy

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (13)

• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum

  4 weeks

• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum

  3 months

• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum

  6 months

• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum

  12 months

• Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum

  2 years

Study Arms (4)

AAV8hAAT(AVL) - 5x10¹¹ gc/kg

EXPERIMENTAL

Lowest dose of vector genome copies per kilogram

Biological: AAV8hAAT(AVL)

AAV8hAAT(AVL) - 2x10¹² gc/kg

EXPERIMENTAL

Biological: AAV8hAAT(AVL)

AAV8hAAT(AVL) - 5x10¹² gc/kg

EXPERIMENTAL

Biological: AAV8hAAT(AVL)

AAV8hAAT(AVL) - 2x10¹³ gc/kg

EXPERIMENTAL

Highest dose of vector genome copies per kilogram

Biological: AAV8hAAT(AVL)

Interventions

AAV8hAAT(AVL) BIOLOGICAL

AAV8hAAT(AVL) gene transfer vector

AAV8hAAT(AVL) - 2x10¹² gc/kg; AAV8hAAT(AVL) - 2x10¹³ gc/kg; AAV8hAAT(AVL) - 5x10¹² gc/kg; AAV8hAAT(AVL) - 5x10¹¹ gc/kg

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

WCMC Department of Genetic Medicine

New York, New York, 10021, United States

RECRUITING

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency; Emphysema

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Ronald G Crystal, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Niamh Savage

CONTACT

646-962-5527; nis2049@med.cornell.edu

Sandra Hyde

CONTACT

646-962-2672; sah2003@med.cornell.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2025
• First Posted: May 30, 2025
• Study Start: February 26, 2025
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): August 1, 2032
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: At the time of publication, and after final analyses have been completed.
• 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

Locations

US (1)