Gene Therapy for Cardiomyopathy in Friedreich's Ataxia

Recruiting at 3 trial locations

Overseen By LEXEO Clinical Trials

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Lexeo Therapeutics

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Diabetes, Liver dysfunction, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

8 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2, open-label, dose-ascending, multicenter study of the safety and efficacy of LX2006 for participants who have Friedreich's Ataxia with evidence of cardiomyopathy. The study will evaluate up to three doses of single administration of LX2006 (AAVrh.10hFXN), an adeno-associated virus (AAV) gene therapy designed to intravenously deliver the human frataxin (hFXN) gene to cardiac cells over a 52-week period. Long-term safety and efficacy will be evaluated for an additional 4-years for a total of 5-years post LX2006 treatment.

Do I need to stop my current medications for the trial?

The trial excludes participants who are taking systemic corticosteroids or other immunosuppressive medications, so you may need to stop these if you are currently taking them. The protocol does not specify about other medications.

What data supports the effectiveness of the treatment LX2006 for cardiomyopathy in Friedreich's Ataxia?

Research on similar gene therapies using adeno-associated viruses (AAV) for Duchenne muscular dystrophy (DMD) shows promise in improving heart function and reducing cardiac issues. These studies suggest that AAV-based gene therapy can be effective in treating heart-related conditions, which may indicate potential benefits for cardiomyopathy in Friedreich's Ataxia. ^{1 2 3 4 5}

Is the gene therapy treatment LX2006 generally safe in humans?

Research on similar gene therapies using adeno-associated virus (AAV) vectors, like those for Duchenne muscular dystrophy, shows they are generally safe and well-tolerated in humans, with no significant immune response observed in clinical trials. ^{1 2 5 6 7}

How does the treatment LX2006 differ from other treatments for Friedreich's Ataxia cardiomyopathy?

LX2006 is a gene therapy that uses an adeno-associated virus (AAV) to deliver a normal copy of the frataxin gene directly to heart cells, aiming to correct the underlying genetic cause of cardiomyopathy in Friedreich's Ataxia. This approach is unique because it targets the root cause of the disease at the genetic level, unlike other treatments that may only address symptoms. ^{8 9 10 11 12}

Research Team

LEXEO Clinical Trials

Principal Investigator

Lexeo Therapeutics

Eligibility Criteria

This trial is for individuals with Friedreich's Ataxia diagnosed before age 25 who have heart issues related to the condition. They must meet specific criteria for cardiomyopathy and antibody levels. Excluded are those with significant coronary disease, uncontrolled diabetes or psychiatric conditions, abnormal liver function, certain infections like hepatitis or HIV, unstable heart rhythms needing intervention, or on immunosuppressive drugs.

Inclusion Criteria

Your levels of specific antibodies need to be within certain ranges as outlined in the study protocol.

You have specific heart problems described in the study protocol.

I was diagnosed with Fanconi anemia before I turned 25.

Exclusion Criteria

You have a mental health condition that is not being well managed.

My diabetes is not under control.

I have heart disease not related to FA cardiomyopathy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single administration of LX2006 gene therapy, with dose escalation across cohorts

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• LX2006

Trial Overview The study tests LX2006 gene therapy at different doses in people with Friedreich's Ataxia-related cardiomyopathy. It involves a single administration of an AAV vector carrying the human frataxin gene to cardiac cells and monitors safety and effectiveness over one year, with a follow-up period extending to five years.

Participant Groups

Group I: Cohort 1/ Cohort 2/ Cohort 3 Experimental Treatment 3 Interventions

Who Is Running the Clinical Trial?

Lexeo Therapeutics

Lead Sponsor

Trials

5

Recruited

110+

Findings from Research

The micro-dystrophin gene transfer using rAAVrh74.MHCK7 was found to be well tolerated in a phase 1/2a trial with four young patients, showing only mild to moderate adverse events and no serious complications over one year.

All patients demonstrated significant expression of micro-dystrophin in muscle fibers and improvements in functional measures, such as North Star Ambulatory Assessment scores and reduced creatine kinase levels, indicating potential benefits beyond standard care for Duchenne muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. Mendell, JR., Sahenk, Z., Lehman, K., et al.[2021]

The clinical trial demonstrated that the chimeric AAV2.5 vector is safe and well tolerated in boys with Duchenne muscular dystrophy (DMD), with no cellular immune response detected against the AAV2.5 capsid.

AAV2.5 showed effective gene transfer, with recombinant AAV genomes found in all patients, indicating its potential for efficient muscle transduction and paving the way for future gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Bowles, DE., McPhee, SW., Li, C., et al.[2022]

In a study of 48 pediatric patients with Friedreich's ataxia, 85% showed elevated left ventricular mass, indicating a common subclinical hypertrophic cardiomyopathy despite normal heart function as measured by ejection fraction.

Concentric hypertrophy was found in 44% of subjects and was specifically linked to significant diastolic and systolic dysfunction, highlighting the need for cardiac monitoring in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population. Plehn, JF., Hasbani, K., Ernst, I., et al.[2019]

The study developed a cardiac-specific mouse model of Friedreich's ataxia (FA) that mimics the human condition, showing normal heart function at rest but significant dysfunction under stress, which is crucial for testing potential therapies.

A single intravenous treatment with an AAV vector delivering the human frataxin gene successfully corrected the cardiac dysfunction in the mouse model, restoring heart performance to levels similar to healthy controls, indicating the potential efficacy of gene therapy for FA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy. Salami, CO., Jackson, K., Jose, C., et al.[2023]

Genome editing using zinc finger nucleases to correct the expanded GAA repeats in the FXN gene of Friedreich's ataxia (FRDA) patients significantly upregulated frataxin expression and reversed pathological changes in cardiomyocytes derived from induced pluripotent stem cells (iPSCs).

The study demonstrated that iPSC-derived FRDA cardiomyocytes exhibit distinct molecular defects associated with cardiomyopathy, which can be effectively corrected through genome editing, highlighting the potential for this approach as a future therapeutic strategy for FRDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes. Li, J., Rozwadowska, N., Clark, A., et al.[2023]

AAVrh.10hFXN, an adeno-associated virus vector delivering the human frataxin gene, shows promise in treating cardiac issues in Friedreich's ataxia, with a significant improvement in heart function and mortality observed at a dose of 1.8 × 10^12 gc/kg in a mouse model.

The study identified effective dosing levels that can achieve frataxin levels comparable to healthy human heterozygotes, suggesting potential for safe and effective treatment in larger animal models, paving the way for future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. Munoz-Zuluaga, C., Gertz, M., Yost-Bido, M., et al.[2023]

In a study on Friedreich ataxia, it was found that transducing only 30% of cardiomyocytes with gene therapy can still provide meaningful therapeutic effects, while full cardiac function recovery requires about 50% transduction.

The study highlights that the therapeutic benefits of gene therapy are achieved through mechanisms that maintain mitochondrial health in treated cells, and even neighboring untreated cells can experience increased survival, suggesting a broader impact of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms. Belbellaa, B., Reutenauer, L., Monassier, L., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Study on the recombinant adeno-associated virus vector carrying LacZ gene expression in the skeletal muscle]. [2007]

4. United States pubmed.ncbi.nlm.nih.gov

AAV genome loss from dystrophic mouse muscles during AAV-U7 snRNA-mediated exon-skipping therapy. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Long-term preservation of cardiac structure and function after adeno-associated virus serotype 9-mediated microdystrophin gene transfer in mdx mice. [2012]

6. United States pubmed.ncbi.nlm.nih.gov

Cardiac expression of a mini-dystrophin that normalizes skeletal muscle force only partially restores heart function in aged Mdx mice. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms. [2023]