Gene Therapy for Diastolic Heart Failure

(MUSIC-HFpEF Trial)

Recruiting at 1 trial location

Overseen By Sardocor

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sardocor Corp.

Must be taking: Diuretics

Disqualifiers: Atrial fibrillation, Severe COPD, Cancer, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

10 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 AAV1/SERCA2a for individuals with diastolic heart failure, a condition where the heart struggles to relax and fill with blood. The main goals are to determine the therapy's safety and its effectiveness in improving heart relaxation during exercise. Participants will receive a one-time treatment and undergo monitoring over time. Ideal candidates for the trial are those diagnosed with heart failure that impacts daily activities and who are currently taking diuretic pills to manage symptoms. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new therapy.

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.

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

Research has shown that the gene therapy AAV1/SERCA2a was tested in a small group of heart failure patients. In a study with five participants over three years, the treatment successfully delivered the gene to their hearts. Importantly, researchers reported no serious safety issues during this time.

The therapy aims to improve heart function by boosting the activity of a protein called SERCA2a, which often underperforms in people with heart failure.

Although this study was small, the absence of major safety problems is encouraging. As this is an early-stage trial, the main focus is on ensuring the treatment is safe and well-tolerated. Further research will help confirm these findings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for diastolic heart failure focus on managing symptoms using medications like diuretics, beta-blockers, or ACE inhibitors. But AAV1/SERCA2a works differently, targeting the heart muscle at the genetic level. This gene therapy uses a virus (AAV1) to deliver the SERCA2a gene directly into heart cells, aiming to improve their function. Researchers are excited because this approach could potentially repair the underlying heart issue rather than just alleviating symptoms, offering a groundbreaking way to treat heart failure.

What evidence suggests that this gene therapy might be an effective treatment for diastolic heart failure?

Research shows that the gene therapy AAV1/SERCA2a, which participants in this trial may receive, is designed to increase the activity of a protein called SERCA2a. This protein helps heart muscle cells manage calcium, essential for proper heart contraction and relaxation. In heart failure, SERCA2a activity often decreases, leading to issues with blood filling the heart. Early studies have shown that delivering AAV1/SERCA2a to the heart can successfully raise SERCA2a levels. This approach aims to improve the heart's relaxation during blood filling, addressing a major problem in diastolic heart failure. Although still in the early stages, this research shows promise by focusing on enhancing the heart's calcium management. ^{1 3 4 5 6}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• AAV1/SERCA2a

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06061549

Study Details | NCT06061549 | Modulation of SERCA2a ... The goal of this clinical trial is to test an experimental gene therapy in participants with heart failure with preserved ejection fraction, also known as ...

2. nature.com nature.com/articles/s41434-020-0171-7

Investigation of the safety and feasibility of AAV1/SERCA2a ... Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11991975/

SERCA2a dysfunction in the pathophysiology of heart failure ... This review examines the conflicting evidence present for changes in SERCA2a expression and activity in HFpEF, explores potential underlying mechanisms,

4. delta.larvol.com delta.larvol.com/Products/?ProductId=e4c3a5bb-a333-4202-bdc5-37563d0b857b

Mydicar (AAV1/SERCA2a) / Eiger, Armata, Theragene A Phase 1 Clinical Trial of High Dose AAV1.SERCA2a in Patients with Heart Failure: Modulation of SERCA2a of Intra-myocytic Calcium trafficking in Heart Failure ...

5. cgtlive.com cgtlive.com/view/gene-therapy-heart-failure-with-preserved-ejection-fraction-trial

Gene Therapy to be Assessed in Heart Failure With ... SRD-001 is designed to increase expression and functional activity of SERCA2a, down-regulation of which is associated with all forms of heart failure.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06061549?term=SERCA2a&viewType=Table&rank=6

Study Details | Modulation of SERCA2a of Intra-myocytic ... The goal of this clinical trial is to test an experimental gene therapy in participants with heart failure with preserved ejection fraction, also known as ...