Gene Therapy for Cardiomyopathy in Friedreich's Ataxia

Overseen By Niamh Savage, BS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Weill Medical College of Cornell University

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Diabetes, Heart failure, Hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Single administration

25 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety and preliminary efficacy of AAVrh.10hFXN to treat the cardiomyopathy associated with Friedreich's ataxia (FA). AAVrh.10hFXN is a serotype rh.10 adeno-associated virus gene transfer vector coding for Frataxin (FXN). The drug is administered intravenously. This is a phase 1, open label, dose escalation study with a total of 25 participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on corticosteroids or other immunosuppressive drugs. You also cannot participate if you have been on experimental medications in the last 12 weeks.

What data supports the effectiveness of the treatment AAVrh.10hFXN for cardiomyopathy in Friedreich's Ataxia?

Research shows that AAVrh.10hFXN, a gene therapy, improved heart function and survival rates in animal models of Friedreich's Ataxia by increasing levels of frataxin, a protein that is deficient in this condition. In particular, a specific dose of this treatment significantly improved heart function and reduced mortality in mice, and achieved target protein levels in nonhuman primates, suggesting its potential effectiveness in humans. ^{1 2 3 4 5}

Is gene therapy using AAV vectors generally safe for humans?

Gene therapy using AAV vectors has been tested in various conditions, and while some trials have shown it to be safe and well-tolerated, others have reported serious adverse events, including inflammation of the muscles and heart, and even deaths in some cases. It's important to consider these risks and discuss them with your healthcare provider. ^{6 7 8 9 10}

How is the treatment AAVrh.10hFXN (LX2006) for Friedreich's Ataxia different from other treatments?

AAVrh.10hFXN (LX2006) is a gene therapy that uses a viral vector to deliver a healthy copy of the FXN gene directly to the heart, which is unique compared to other treatments that may not target the genetic cause of cardiomyopathy in Friedreich's Ataxia. This approach aims to address the underlying genetic defect rather than just managing symptoms. ^{11 12 13 14 15}

Research Team

Ronald G Crystal, MD

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

Adults aged 18-50 with Friedreich's ataxia and related heart issues, who have a specific genetic marker (>600 GAA repeats), can join this trial. They must be able to undergo cardiac MRI, not be on immunosuppressants or other trials for 12 weeks prior, and use birth control if fertile. Exclusions include life-threatening conditions, uncontrolled diabetes or arrhythmias, low blood counts, past gene therapy participation, certain cancers within five years, severe heart failure or psychiatric disease.

Inclusion Criteria

Willing and able to provide informed consent

My genetic test shows more than 600 GAA repeats in one allele.

My heart's pumping ability is within the normal range.

Exclusion Criteria

Pregnant or breastfeeding woman

Prior participation in any gene and/or cell therapy

I have been diagnosed with blocked arteries in my heart.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AAVrh.10hFXN gene therapy intravenously in a dose escalation study

Single administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in cardiopulmonary exercise testing and cardiac imaging

5 years

Treatment Details

Interventions

• AAVrh.10hFXN
• Prednisone

Trial Overview This phase IA study tests AAVrh.10hFXN gene therapy's safety and initial effectiveness in treating cardiomyopathy caused by Friedreich's ataxia. It involves an intravenous drug that delivers the FXN gene directly into patients' cells. The trial is open-label (patients know what they're getting) and gradually increases doses among ten participants to find the safest dose.

Participant Groups

Group I: Third Dose Cohort Experimental Treatment 2 Interventions

AAVrh.10hFXN will be administered intravenously.

Group II: Second Dose Cohort Experimental Treatment 2 Interventions

AAVrh.10hFXN will be administered intravenously.

Group III: Maximum Tolerated Dose Cohort Experimental Treatment 2 Interventions

AAVrh.10hFXN will be administered intravenously.

Group IV: First Dose Cohort Experimental Treatment 2 Interventions

AAVrh.10hFXN will be administered intravenously.

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+

Findings from Research

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]

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]

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]

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]

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]

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]

The long-term safety of AAV2-REP1 in choroideremia patients showed some adverse effects, including localized intraretinal immune responses and permanent retinal damage, raising concerns about its effectiveness in late-stage disease.

Antisense oligonucleotide (ASO) therapy demonstrated potential benefits, recovering significant amounts of normal RNA and protein in fibroblasts from trial patients, suggesting it may be a promising alternative treatment for certain subgroups of choroideremia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy. Zhai, Y., Xu, M., Radziwon, A., et al.[2023]

In a phase I/II clinical trial involving 15 patients with choroideremia, subretinal delivery of the AAV2-hCHM vector was found to be safe, with no vector-related or systemic toxicities reported over a 2-year follow-up period.

Visual acuity remained stable within 15 letters of baseline in 13 out of 15 patients, although two patients experienced complications, indicating a potential risk associated with the injection procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial. Aleman, TS., Huckfeldt, RM., Serrano, LW., et al.[2022]

First-generation AAV vectors, including AAV9 and AAVrh74, showed limited efficacy and serious safety concerns in clinical trials for Duchenne muscular dystrophy, with adverse events including patient deaths and myositis.

Optimized AAVrh74 vectors, modified for better performance, demonstrated significantly improved efficiency in delivering genes to human skeletal muscle cells in laboratory tests and in mouse models, suggesting they could be a safer and more effective option for gene therapy in muscle diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of capsid- and genome-modified optimized AAVrh74 vectors for muscle gene therapy. Shoti, J., Qing, K., Keeler, GD., et al.[2023]

A new approach using tri-AAV vectors successfully delivered the full-length human dystrophin gene, which is crucial for treating Duchenne muscular dystrophy (DMD), by splitting the gene into three parts and packaging them separately due to AAV's size limitations.

This study demonstrated that AAV can be engineered to carry larger genes (up to 15 kb), which opens up possibilities for more effective gene therapies for conditions like DMD, although further optimization is needed for better efficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Full-length dystrophin reconstitution with adeno-associated viral vectors. Lostal, W., Kodippili, K., Yue, Y., et al.[2022]

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]

Using recombinant adeno-associated virus (rAAV) vectors to deliver functional GAA genes significantly increased GAA enzyme activity in both Pompe patient cells and animal models, with a 10-fold increase observed in GAA-deficient myotubes.

In animal studies, treatment with rAAV vectors not only restored near-normal enzyme activity in Gaa(-/-) mice but also improved muscle function, indicating the potential of this gene therapy approach for treating Pompe disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Fraites, TJ., Schleissing, MR., Shanely, RA., et al.[2017]

A novel gene therapy using two AAV vectors has shown promising results in a mouse model of Oculopharyngeal Muscular Dystrophy (OPMD), reversing muscle atrophy and insoluble protein aggregates, which are key features of the disease.

This gene therapy approach not only prevents further muscle damage but also stabilizes muscle strength to levels comparable to healthy muscles, suggesting potential for effective treatment in humans with OPMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Established PABPN1 intranuclear inclusions in OPMD muscle can be efficiently reversed by AAV-mediated knockdown and replacement of mutant expanded PABPN1. Malerba, A., Klein, P., Lu-Nguyen, N., et al.[2020]

A gene therapy approach using an adeno-associated virus (AAV)-based trans-splicing vector successfully generated wild-type GNE transcripts in muscle cells from a patient with GNE myopathy, indicating potential for correcting the common M712T mutation.

This study provides proof of concept for using trans-splicing as a genetic therapy strategy for GNE myopathy, paving the way for future in vivo research in animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of the Middle Eastern M712T mutation causing GNE myopathy by trans-splicing. Tal-Goldberg, T., Lorain, S., Mitrani-Rosenbaum, S.[2021]

A new murine model of Infantile-onset Pompe Disease (IOPD) was created using CRISPR-Cas9 technology, accurately mimicking the severe hypertrophic cardiomyopathy and skeletal muscle weakness seen in human IOPD, which is crucial for testing new treatments.

This model shows specific genetic alterations without off-target effects, making it a valuable tool for evaluating potential therapies for IOPD, as it retains key disease characteristics that were lacking in previous models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 generated Pompe knock-in murine model exhibits early-onset hypertrophic cardiomyopathy and skeletal muscle weakness. Huang, JY., Kan, SH., Sandfeld, EK., et al.[2022]

References

1. 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]

2. 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]

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

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

4. England pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy. [2023]

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

Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial. [2022]

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

Development of capsid- and genome-modified optimized AAVrh74 vectors for muscle gene therapy. [2023]

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

Full-length dystrophin reconstitution with adeno-associated viral vectors. [2022]

11. 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]

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

Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. [2017]

13. England pubmed.ncbi.nlm.nih.gov

Established PABPN1 intranuclear inclusions in OPMD muscle can be efficiently reversed by AAV-mediated knockdown and replacement of mutant expanded PABPN1. [2020]

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

Correction of the Middle Eastern M712T mutation causing GNE myopathy by trans-splicing. [2021]

15. England pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 generated Pompe knock-in murine model exhibits early-onset hypertrophic cardiomyopathy and skeletal muscle weakness. [2022]