Gene Therapy for Alpha-1 Antitrypsin Deficiency

Overseen By Sandra Hyde

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Weill Medical College of Cornell University

Must not be taking: Corticosteroids, Immunosuppressants, Beta-blockers, others

Disqualifiers: Immunodeficiency, Cardiovascular disease, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 1 day

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy for individuals with alpha-1 antitrypsin deficiency, a condition that can lead to lung issues like emphysema. The goal is to determine if a single dose of the therapy can safely and effectively protect the lungs by providing a resistant form of the AAT protein. Participants will receive varying doses to identify the optimal one. The trial seeks individuals with a specific genetic type of AAT deficiency and mild to moderate lung function loss due to emphysema. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot participate if you are on systemic corticosteroids, immunosuppressive medications, beta-blockers, or other cardiac therapy drugs. If you are on these medications, you would need to stop them to join the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Earlier studies have shown that the gene therapy AAV8hAAT(AVL) is safe for humans. Research indicates that no major side effects occurred, even with varying doses. This suggests that the therapy did not directly cause serious side effects. The treatment aims to help individuals with alpha-1 antitrypsin deficiency, a condition that can lead to lung problems. So far, the therapy appears well-tolerated, making it a promising option for potential trial participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Alpha-1 Antitrypsin Deficiency, which often involve enzyme replacement therapy or lung transplants, AAV8hAAT(AVL) offers a novel approach by using gene therapy. This treatment introduces a new mechanism of action by delivering a healthy copy of the gene responsible for producing the Alpha-1 Antitrypsin protein directly to the patient's cells using an adeno-associated virus vector. Researchers are excited about this approach because it has the potential to provide a long-lasting solution by addressing the root cause of the deficiency, rather than just managing symptoms, potentially leading to fewer interventions over time.

What evidence suggests that this gene therapy might be an effective treatment for alpha-1 antitrypsin deficiency?

Research has shown that a gene therapy called AAV8hAAT(AVL) might help treat alpha-1 antitrypsin deficiency. In animal studies, this therapy safely delivered a modified version of the AAT protein that remains in the body longer. The goal is to correct the protein issue that causes lung damage in individuals with this condition. The modified AAT protein is more stable and less prone to damage. Although human studies provide limited information, these early results suggest it could offer long-term lung protection. Participants in this trial will receive different doses of AAV8hAAT(AVL) to evaluate its safety and effectiveness. ^{5 6 7 8 9}

Who Is on the Research Team?

Ronald G Crystal, MD

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for individuals with Alpha-1 Antitrypsin Deficiency, a genetic condition that can cause lung and liver disease. Participants should be adults who have confirmed deficiency and are willing to undergo gene therapy. Specific inclusion and exclusion criteria details are not provided.

Inclusion Criteria

Troponin T within normal limits

My lung function is mildly to moderately reduced, and I have emphysema.

My kidney function is normal.

Exclusion Criteria

I am allergic to certain drugs used in lung exams.

I am taking steroids or other drugs that affect my immune system for a condition I already had.

Prior history of hypersensitivity or anaphylaxis associated with the administration of any AAT product

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single administration of AAV8hAAT(AVL) gene therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular visits over 5 years

What Are the Treatments Tested in This Trial?

Interventions

• AAV8hAAT(AVL)

Trial Overview The study tests a single administration of AAV8hAAT(AVL), which is a gene therapy designed to deliver an oxidation-resistant form of the AAT protein directly into the bloodstream, aiming for persistent protection of the lungs.

How Is the Trial Designed?

Group I: AAV8hAAT(AVL) - 5x10¹¹ gc/kg Experimental Treatment 1 Intervention

Lowest dose of vector genome copies per kilogram

Group II: AAV8hAAT(AVL) - 5x10¹² gc/kg Experimental Treatment 1 Intervention

Group III: AAV8hAAT(AVL) - 2x10¹³ gc/kg Experimental Treatment 1 Intervention

Highest dose of vector genome copies per kilogram

Group IV: AAV8hAAT(AVL) - 2x10¹² gc/kg Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Citations

1. reporter.nih.gov reporter.nih.gov/search/g_X-qd1kDUSA5toi9b_Jzw/project-details/11328632

Gene Therapy for Alpha 1-Antitrypsin Deficiency A toxicology study over 6 months in C57Bl/6 mice demonstrated that IV administration of AAV8hAAT(AVL) is safe. Based on the preclinical efficacy and safety data ...

2. liebertpub.com liebertpub.com/doi/10.1089/hum.2022.192

Safety of Intravenous Administration of an AAV8 Vector ... This study demonstrates that AAV8hAAT(AVL) has a safety profile consistent with the requirements for proceeding to a clinical study.

3. app.trialscreen.org app.trialscreen.org/trials/phase-1-gene-therapy-alpha-antitrypsin-deficiency-trial-nct06996756

Gene Therapy for Alpha-1 Antitrypsin Deficiency This Interventional study is looking for people with Alpha 1-Antitrypsin Deficiency in New York United States to take part.

4. insight.jci.org insight.jci.org/articles/view/135951

Gene therapy for alpha 1-antitrypsin deficiency with an ... The data demonstrate that in vivo gene therapy with AAT with modified M351 to V and M358 to L (AAT-AVL) results in persistent expression of AAT ...

5. trial.medpath.com trial.medpath.com/clinical-trial/2981d71ad5ad1b1a/nct06996756-gene-therapy-alpha-1-antitrypsin-deficiency

Gene Therapy for Alpha-1 Antitrypsin Deficiency - MedPath 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9963503/

Safety of Intravenous Administration of an AAV8 Vector ... The data demonstrate that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effect attributed to AAV8hAAT(AVL) vector at any dose.

7. journals.sagepub.com journals.sagepub.com/doi/abs/10.1089/hum.2022.192

Safety of Intravenous Administration of an AAV8 Vector ... α1-antitrypsin (AAT) deficiency is a common autosomal recessive hereditary disorder, with a high risk for the development of early-onset panacinar emphysema ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36606685/

Safety of Intravenous Administration of an AAV8 Vector ... The data demonstrate that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effect attributed to AAV8hAAT(AVL) vector at any dose.

9. avancebio.com avancebio.com/weill-cornell-study-demonstrates-safety-of-intravenous-administration-of-an-aav8-gene-therapy/

Weill Cornell study demonstrates safety of intravenous ... The data demonstrates that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effects attributed to AAV8hAAT(AVL) vector at any ...