Gene Therapy for Right Ventricular Cardiomyopathy

(RIDGE-1 Trial)

Recruiting at 16 trial locations

Overseen By Matthew Pollman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Tenaya Therapeutics

Disqualifiers: Myocardial infarction, Heart failure, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called TN-401, designed to help people with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Researchers aim to determine if the treatment is safe and beneficial for those with a specific genetic change (PKP2 mutation) linked to this condition. Individuals who frequently experience irregular heartbeats and have an implantable defibrillator might be suitable candidates. The trial includes two groups, each receiving different doses of the therapy to assess its effects. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that TN-401 gene therapy is likely to be safe for humans?

Research shows that TN-401 gene therapy is undergoing safety testing in individuals with ARVC, a heart condition linked to a PKP2 mutation. Earlier studies selected the delivery method for TN-401, known as AAV9, due to extensive safety data supporting it. Other research has proven this method safe.

In a recent study, the first group of patients received a lower dose of TN-401, and safety reviews have been positive, indicating the treatment was well-tolerated at that dose. Although more information is needed, these early results are promising for TN-401's safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cardiomyopathy?

Researchers are excited about TN-401 for treating right ventricular cardiomyopathy because it uses gene therapy to directly target the genetic cause of the disease. Unlike traditional treatments that manage symptoms of cardiomyopathy, such as beta-blockers or ACE inhibitors, TN-401 aims to correct the underlying defect by delivering a healthy copy of the gene. This innovative approach has the potential to offer long-term benefits and possibly a cure, rather than just temporary relief, making it a groundbreaking option in the field of heart disease treatment.

What evidence suggests that TN-401 gene therapy might be an effective treatment for ARVC?

Research has shown that TN-401 gene therapy could help treat ARVC, a heart condition caused by the PKP2 gene mutation. Animal studies found that this therapy can stabilize heart rhythms and slow disease progression. TN-401 uses a virus to deliver a healthy PKP2 gene directly to heart cells. Early human trials also showed improvements in heart function, such as better heart pumping. Although human data remains limited, these results suggest that TN-401 might help manage symptoms and improve heart health in people with this genetic mutation. Participants in this trial will receive TN-401 at different doses: Cohort 1 will receive 3E13 vg/kg, and Cohort 2 will receive 6E13 vg/kg, to evaluate its effectiveness and safety. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• TN-401

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.

How Is the Trial Designed?

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

TN-401 is already approved in United States, United Kingdom for the following indications:

Approved in United States as TN-401 for:

• PKP2 mutation-associated arrhythmogenic right ventricular cardiomyopathy (ARVC)

Approved in United Kingdom as TN-401 for:

• PKP2 mutation-associated arrhythmogenic right ventricular cardiomyopathy (ARVC)

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. investors.tenayatherapeutics.com investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-doses-first-patient-ridgetm-1-phase-1b

1 Phase 1b Clinical Trial of TN-401 for the Treatment of PKP2 ... Compared to untreated in vivo knock-out models, TN-401 normalized heart rhythms, reversed disease progression and extended survival following a ...

2. heartrhythmjournal.com heartrhythmjournal.com/article/S1547-5271(25)01734-5/fulltext

PO-05-115 DETERMINING ELIGIBILITY FOR RIDGETM ... TN-401 utilizes a AAV9-capsid to deliver the functional PKP2 gene to heart muscle cells. AAV9 was selected as the gene therapy delivery capsid for TN-401 based ...

3. nature.com nature.com/articles/s41591-025-04011-z

Cardiotropic AAV gene therapy for heart failure: a phase 1 ... The preliminary assessments of efficacy outcomes showed improvements in the New York Heart Association class and left ventricular ejection ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06228924

NCT06228924 | Open-label, Dose Escalation Study of ... 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 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11201581/

Exploring the Therapeutic Potential of Gene Therapy in ... This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages.

6. investors.tenayatherapeutics.com investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-receives-positive-safety-reviews-independent-dsmbs

Tenaya Receives Positive Safety Reviews from Independent ... Tenaya enrolled the first three patients (Cohort 1) at the 3E13 vg/kg dose in the RIDGE-1 Phase 1b clinical trial of TN-401 for the potential ...

7. heart.bmj.com heart.bmj.com/content/111/Suppl_3/A33.abstract

1-036 RIDGETM-1: a phase 1b interventional study to ... Conclusion If the results of RIDGE-1 show positive safety, tolerability and efficacy results in ARVC adults, Tenaya Therapeutics plans to assess TN-401 in a ...

8. tenayatherapeutics.com tenayatherapeutics.com/tn-401/

TN-401 TN-401 gene replacement therapy is designed address the underlying cause of disease by delivering a working PKP2 gene to the heart. ARVC and Genetics.