Gene Therapy for Right Ventricular Cardiomyopathy

(RIDGE-1 Trial)

Recruiting at 16 trial locations

Overseen By Matthew Pollman, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Tenaya Therapeutics

Disqualifiers: Myocardial infarction, Heart failure, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This first-in-human study is designed to evaluate the safety, and preliminary efficacy (PD) of TN-401 gene therapy in adult patients with symptomatic PKP2 mutation-associated ARVC.

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment TN-401 for Right Ventricular Cardiomyopathy?

Gene therapy has shown promise in improving heart function in conditions like heart failure after a heart attack, suggesting it might also help with other heart issues. Additionally, similar gene therapies have been effective in reducing heart failure progression and improving heart function in animal studies. ^{1 2 3 4 5}

Is gene therapy for heart conditions generally safe in humans?

Gene therapy using adeno-associated vectors has been tested in patients with heart failure and showed no safety concerns, although it did not lead to clinical improvements. However, there are potential safety challenges due to immune responses, which can cause issues like myocarditis (inflammation of the heart muscle). ^{6 7 8 9 10}

How is the treatment TN-401 unique for right ventricular cardiomyopathy?

TN-401 is a gene therapy that uses adeno-associated virus vectors to deliver therapeutic genes to heart cells, which is different from traditional treatments that mainly focus on managing symptoms. This approach aims to correct the underlying genetic causes of cardiomyopathy, offering a potentially more effective and long-term solution. ^{1 11 12 13 14}

Eligibility Criteria

Adults with a specific heart condition called ARVC linked to PKP2 mutations can join this trial. They should have symptoms, a left ventricular ejection fraction of 50% or more, an implantable cardiac defibrillator for at least a year, and frequent premature ventricular contractions. Those in NYHA Functional Class I to III are eligible.

Inclusion Criteria

I often have irregular heartbeats that start in the lower chambers.

My heart condition allows me to perform daily activities with minimal to moderate difficulty.

My heart pumps blood well.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous (IV) dose of TN-401 in one of two planned dose cohorts

1 day

1 visit (in-person)

Dose Escalation Review

Data Safety Monitoring Board (DSMB) reviews safety data to determine if the next dose cohort can be initiated

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• TN-401 (Gene Therapy)

Trial Overview The study is testing TN-401 gene therapy's safety and initial effectiveness on adults with symptomatic ARVC due to PKP2 mutations. It's the first time humans are receiving this treatment.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

Dose for Cohort 2 will be 6E13 vg/kg

Group II: Cohort 1 Experimental Treatment 1 Intervention

Dose for Cohort 1 will be 3E13 vg/kg

Who Is Running the Clinical Trial?

Tenaya Therapeutics

Lead Sponsor

Trials

4

Recruited

450+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Findings from Research

In a study of 235 patients with idiopathic dilated cardiomyopathy (DCM), 43% were found to have familial DCM, with a 5% prevalence of mutations in the TNNC1 and TNNT2 genes, indicating a significant genetic component to the disease.

Mutations in the troponin complex were associated with severe disease expression and complete penetrance, leading to high rates of adverse outcomes, including cardiac transplantation and sudden death, highlighting the importance of genetic testing for early identification and management of at-risk individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. Mogensen, J., Murphy, RT., Shaw, T., et al.[2022]

Preclinical studies indicate that gene transfer can effectively improve heart function and reduce harmful changes in the heart after a heart attack, suggesting potential benefits for patients with congestive heart failure (CHF).

Gene therapy could be personalized for individual patients and, when combined with existing treatments, offers hope for better management of CHF, which affects around 23 million people globally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for myocardial infarction-associated congestive heart failure: how far have we got? Hammond, HK., Tang, T.[2021]

In a study of 80 patients with idiopathic dilated cardiomyopathy (DCM), specific genetic variations in cytokine genes were linked to disease severity, with TGF-β1 +869 T/C polymorphism showing that homozygous TT patients had significantly higher exercise capacity (VO2 max) compared to CC homozygous patients, particularly in those under 39 years old.

The TGF-β1 +915 G/C polymorphism was associated with a 4.2 times higher likelihood of being in a worse NYHA functional class (III-IV), indicating that certain genetic markers can help predict prognosis and severity in DCM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy. Adamopoulos, S., Kolokathis, F., Gkouziouta, A., et al.[2011]

In a mouse model of heart failure, ectopic expression of the RXFP1 receptor and subsequent treatment with the hormone relaxin (RLN) significantly improved heart function and reduced the progression of heart failure, indicating a potential new therapy for this condition.

The study demonstrated that RLN activates RXFP1 signaling, leading to specific phosphorylation of proteins that enhance heart muscle contractility, suggesting a novel mechanism of action distinct from traditional heart failure treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ligand-activated RXFP1 gene therapy ameliorates pressure overload-induced cardiac dysfunction. Sasipong, N., Schlegel, P., Wingert, J., et al.[2022]

In a study of 26 dogs with congestive heart failure (CHF) due to myxomatous mitral valve disease, a treatment algorithm that increased diuretic or pimobendan usage significantly reduced NT-proBNP levels in dogs with elevated baseline levels (≥1500 pmol/L).

The treatment escalation based on NT-proBNP levels was effective without causing significant changes in kidney function markers, indicating a safe approach to managing CHF in dogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease. Hezzell, MJ., Block, CL., Laughlin, DS., et al.[2021]

The titratable two-step transcriptional amplification (tTSTA) vector strategy allows for significant modulation of gene expression in the heart, achieving up to a tenfold increase in expression with the use of raloxifene after intramyocardial injection.

This approach demonstrated tissue-specific effects, as hydrodynamic tail vein injection resulted in negligible long-term gene expression in the liver, highlighting the potential for safer cardiac gene therapy with minimized off-target effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor. Chen, IY., Paulmurugan, R., Nielsen, CH., et al.[2021]

Two novel AAV capsid variants, AAV2-THGTPAD and AAV2-NLPGSGD, were identified as more effective than the standard AAV2 and AAV9 in delivering gene therapy specifically to heart cells, showing improved transduction efficiency in a mouse model of cardiac hypertrophy.

These variants also demonstrated reduced immunogenicity, meaning they are less likely to be neutralized by the immune system, which enhances their potential for safe and effective cardiac-directed gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes. Rode, L., Bär, C., Groß, S., et al.[2023]

The study demonstrated that the MCARD method for delivering scAAV6-βARKct in sheep allows for stable and specific cardiac delivery, with a half-life of approximately 2.66 minutes and complete clearance from the system within one week.

There is a positive correlation between vector exposure and in vivo transduction, indicating that MCARD could help establish an effective therapeutic window for gene therapy in heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window. Fargnoli, AS., Katz, MG., Yarnall, C., et al.[2021]

Gene therapy has made significant advancements in treating conditions like Leber congenital amaurosis, hemophilia, and spinal muscular atrophy, primarily using adeno-associated vectors that are both efficient and safe.

While myocardial gene therapy has been tested in heart failure patients without safety issues, it has not yet shown clinical improvements, but ongoing adaptations in delivery systems and targets suggest potential for future success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Cardiac Gene Therapy. Ishikawa, K., Weber, T., Hajjar, RJ.[2020]

Adeno-associated virus (AAV)-mediated gene therapy is a leading method for treating inherited cardiomyopathies, showing promise in clinical trials for correcting genetic abnormalities.

However, immune responses to the AAV virus and the introduced gene can pose significant safety challenges, particularly the risk of myocarditis, highlighting the need for improved delivery methods and safety measures in gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy vector-related myocarditis. Silver, E., Argiro, A., Hong, K., et al.[2023]

Dilated cardiomyopathy (DCM) is a serious heart disease with high rates of incidence and mortality, primarily managed through symptom relief and heart transplantation.

The study suggests that targeting the cardiac troponin I type 3 interacting kinase (TNI3K) gene with CRISPR/Cas9 gene therapy could be a promising approach to treat DCM, as TNI3K is linked to superoxide production in affected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR/Cas 9 system for the treatment of dilated cardiomyopathy: A hypothesis related to function of a MAP kinase. Olivaes, J., Bonamino, MH., Markoski, MM.[2019]

Animal models of inherited cardiomyopathies, such as juvenile dilated cardiomyopathy in Portuguese water dogs, provide valuable opportunities to test gene therapy approaches that could potentially alter the progression of heart disease.

Adeno-associated virus is highlighted as a promising vector for cardiac gene therapy due to its low immunogenicity, which allows for stable expression of therapeutic genes, making it suitable for chronic conditions like cardiomyopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy in large animal models of human cardiovascular genetic disease. Sleeper, MM., Bish, LT., Sweeney, HL.[2019]

In a study using Yucatan minipigs with induced heart failure, a novel gene therapy (BB-R12) that delivers the human ribonucleotide reductase enzyme significantly improved heart function, particularly in the high-dose group, after two months.

No safety or tolerability issues were observed with BB-R12 treatment, suggesting it could be a promising therapeutic option for reversing cardiac dysfunction in heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure. Kadota, S., Carey, J., Reinecke, H., et al.[2022]

This study introduces allele-specific silencing by RNA interference (ASP-RNAi) as a promising therapeutic approach to target specific mutant alleles of the TNNT2 gene associated with hypertrophic and dilated cardiomyopathy.

The research successfully validated different siRNAs that can selectively knock down the mutant TNNT2 alleles (R92Q and R173W) in vitro, paving the way for potential treatments that minimize effects on the normal allele.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allele-specific silencing by RNAi of R92Q and R173W mutations in cardiac troponin T. Migliore, L., Galvagni, F., Pierantozzi, E., et al.[2022]

References

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

Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. [2022]

2. France pubmed.ncbi.nlm.nih.gov

Gene therapy for myocardial infarction-associated congestive heart failure: how far have we got? [2021]

3. England pubmed.ncbi.nlm.nih.gov

Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy. [2011]

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

Ligand-activated RXFP1 gene therapy ameliorates pressure overload-induced cardiac dysfunction. [2022]

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

Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease. [2021]

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

A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor. [2021]

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

AAV capsid engineering identified two novel variants with improved in vivo tropism for cardiomyocytes. [2023]

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

A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window. [2021]

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

Human Cardiac Gene Therapy. [2020]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Gene therapy vector-related myocarditis. [2023]

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

CRISPR/Cas 9 system for the treatment of dilated cardiomyopathy: A hypothesis related to function of a MAP kinase. [2019]

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

Gene therapy in large animal models of human cardiovascular genetic disease. [2019]

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

Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Allele-specific silencing by RNAi of R92Q and R173W mutations in cardiac troponin T. [2022]