Gene Therapy for Diastolic Heart Failure

(MUSIC-HFpEF Trial)

Recruiting at1 trial location

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Sardocor Corp.

Must be taking: Diuretics

Disqualifiers: Atrial fibrillation, Severe COPD, Cancer, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new gene therapy for people with a type of heart failure where the heart struggles to relax and fill with blood. The therapy is given through an infusion directly into the heart. Researchers want to see if it helps the heart work better and if it is safe for patients. Gene therapy has shown promise in treating heart failure, with improvements making it safer and more effective.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require participants to be on oral diuretic therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment AAV1/SERCA2a for diastolic heart failure?

Research shows that gene therapy using AAV1/SERCA2a can improve heart function by restoring the activity of a protein called SERCA2a, which is often reduced in heart failure. Studies in both animals and humans with heart failure have demonstrated improvements in heart function and a reduction in cardiovascular events after treatment with AAV1/SERCA2a. ^{1 2 3 4 5}

Is SERCA2a gene therapy safe for humans?

Research on SERCA2a gene therapy, including trials like CUPID 2 and SERCA-LVAD, has shown no major safety concerns in small groups of patients with heart failure. Although these studies were primarily focused on heart failure, they provide some evidence that the therapy is generally safe in humans. ^{1 2 3 6 7}

How is the treatment AAV1/SERCA2a unique for diastolic heart failure?

AAV1/SERCA2a is a gene therapy that targets the underlying cause of heart failure by restoring the function of SERCA2a, a protein that helps regulate calcium levels in heart cells, which is crucial for proper heart function. Unlike traditional treatments that manage symptoms, this therapy aims to correct the cellular abnormalities in the heart, potentially improving both systolic and diastolic function. ^{1 2 3 4 7}

Research Team

Eligibility Criteria

This trial is for adults with heart failure who still have a good amount of pumping function (ejection fraction ≥ 50%) and symptoms that are not the most severe. They should be able to exercise somewhat, take diuretics, and use birth control if needed. People with severe lung disease, extreme obesity, unstable conditions, major organ dysfunction or specific heart diseases like amyloidosis can't join.

Inclusion Criteria

Willing and able to provide informed consent

My heart condition mildly or moderately affects my daily activities.

Adequate birth control

Exclusion Criteria

You weigh more than 110 pounds for every 4.9 feet of your height.

My heart condition severely limits my physical activity.

I was hospitalized for heart failure in the last 3 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a one-time infusion of the gene therapy in the cardiac catheterization laboratory

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effects on left-sided filling pressures while exercising

52 weeks

Multiple in-person visits and phone calls

Long-term follow-up

Participants continue to be followed for 4 years with bi-annual, semi-structured telephone or in-person questionnaires

4 years

Treatment Details

Interventions

• AAV1/SERCA2a (Gene Therapy)

Trial Overview The study tests a one-time gene therapy infusion called AAV1/SERCA2a to see if it's safe and can help the heart fill better during relaxation. Participants will receive this treatment in a special lab setting and then be monitored closely for one year with follow-ups over phone calls for four more years.

Participant Groups

Group I: SRD-001 Gene Therapy Experimental Treatment 1 Intervention

AAV1/SERCA2a 3E13 vg

Who Is Running the Clinical Trial?

Sardocor Corp.

Lead Sponsor

Trials

3

Recruited

80+

Findings from Research

Gene transfer of SERCA2a using adeno-associated virus significantly improved heart function in rats with chronic heart failure, restoring left ventricular performance to levels comparable to healthy controls after 30 days.

The treatment not only enhanced calcium handling and energy metabolism in the heart but also normalized the expression of cardiac myosin heavy chain isoforms, suggesting a comprehensive therapeutic effect on heart structure and function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adeno-associated viral gene transfer of SERCA2a improves heart function in chronic congestive heart failure rats]. Hui, HP., Li, XY., Liu, XH., et al.[2012]

In a phase 2b trial involving 250 patients with heart failure, the gene therapy AAV1/SERCA2a did not show any improvement in clinical outcomes compared to placebo, with similar rates of recurrent heart failure events over a median follow-up of 17.5 months.

The study found no significant safety concerns associated with AAV1/SERCA2a, but the lack of efficacy suggests that further research is needed to explore gene therapy options for heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Greenberg, B., Butler, J., Felker, GM., et al.[2022]

Restoring SERCA2a expression through gene therapy has shown promising results in improving heart function and calcium handling in both animal models and isolated cardiac cells, indicating its potential as a treatment for heart failure.

A clinical trial is currently underway using adeno-associated virus type 1 to deliver SERCA2a gene therapy to patients with heart failure, which will help assess the safety and effectiveness of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Lipskaia, L., Chemaly, ER., Hadri, L., et al.[2021]

The CUPID study demonstrated that gene therapy using AAV/SERCA2a significantly improved clinical outcomes in patients with advanced heart failure, showing favorable changes after 12 months and a notable reduction in cardiovascular events over 36 months.

No safety concerns were reported with AAV/SERCA2a treatment, and transgene expression was sustained in the heart tissue for up to 31 months, indicating the potential for long-term benefits of this gene transfer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for heart failure. Greenberg, B.[2018]

The AGENT-HF trial, which aimed to assess the effects of AAV1/SERCA2a on heart function in patients with severe heart failure, was terminated early due to neutral results from another trial, leaving only nine patients randomized and limiting the study's power to detect any significant effects.

At the 6-month follow-up, there was no significant difference in left ventricular end-systolic volume between the AAV1/SERCA2a and placebo groups, indicating that the gene therapy did not improve heart function as intended, although no safety issues were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial. Hulot, JS., Salem, JE., Redheuil, A., et al.[2018]

The SERCA-LVAD trial, involving 5 adult chronic heart failure patients, demonstrated that the gene therapy vector AAV1/SERCA2a could be delivered to the heart, with viral DNA detected in 2 patients at follow-up, indicating successful delivery.

Despite the successful delivery of the gene therapy vector, no functional benefits were observed in heart function, and the trial raised important considerations for future gene therapy studies in patients with left ventricular assist devices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL. Lyon, AR., Babalis, D., Morley-Smith, AC., et al.[2021]

Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy shows promise as a treatment for heart failure, potentially acting as a positive inotrope with anti-arrhythmic properties based on laboratory and early clinical evidence.

The review highlights ongoing clinical trials and discusses the rationale and challenges of implementing SERCA2a gene therapy, suggesting it could be a significant advancement in heart failure treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective. Hayward, C., Banner, NR., Morley-Smith, A., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

[Adeno-associated viral gene transfer of SERCA2a improves heart function in chronic congestive heart failure rats]. [2012]

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

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. [2022]

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

Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Gene therapy for heart failure. [2018]

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

Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL. [2021]

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

The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective. [2022]