Gene Therapy for Danon Disease

Recruiting at 5 trial locations

Overseen By Clinical Information

Age: Any Age

Sex: Male

Trial Phase: Phase 2

Sponsor: Rocket Pharmaceuticals Inc.

Disqualifiers: Severe heart failure, Thrombosis, Transplantation, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm Phase 2 trial to evaluate the efficacy and safety of RP-A501, a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene, in male patients with Danon Disease.

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

The trial protocol does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment RP-A501 for Danon Disease?

Research on similar gene therapies using adeno-associated virus (AAV) vectors for other conditions, like Pompe disease and phenylketonuria, shows promise. These studies indicate that AAV-mediated gene therapy can lead to long-term correction of metabolic issues and promote immune tolerance, suggesting potential effectiveness for RP-A501 in treating Danon Disease. ^{1 2 3 4 5}

Is gene therapy using adeno-associated virus (AAV) vectors generally safe in humans?

Research shows that gene therapy using adeno-associated virus (AAV) vectors is generally safe in humans and animals. In studies for different conditions, such as Leber's congenital amaurosis and phenylketonuria in mice, no significant adverse effects were observed, and any minor effects were transient and not harmful. ^{4 6 7 8 9}

How does the treatment RP-A501 for Danon Disease differ from other treatments?

RP-A501 is a gene therapy that uses an adeno-associated virus (AAV) vector to deliver a functional gene to correct the underlying genetic defect, which is a novel approach compared to traditional treatments that may not address the root cause of the disease. ^{4 5 6 10 11}

Research Team

Joseph W Rossano, M.D.

Principal Investigator

Children's Hospital of Philadelphia

Barry Greenberg, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for male patients with Danon Disease, a rare genetic condition. Participants must have a specific gene mutation, good heart pump function (LVEF ≥ 50%), elevated heart stress levels (hsTnI), be at least 8 years old, show signs of thickened heart muscle but normal pumping ability, and be able to follow the study's procedures. They should not need mechanical breathing support or have had certain serious cardiovascular events.

Inclusion Criteria

I am 8 years old or older.

You have a specific heart condition called left ventricular hypertrophy with preserved systolic function.

Your heart is pumping blood normally.

Exclusion Criteria

I have had a stroke, heart attack, or other serious heart-related issues.

I have had a heart, lung, liver, or other organ transplant.

You are currently using or need a machine to help you breathe.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous infusion of RP-A501

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular visits as per protocol

Long-term follow-up

Participants are monitored for long-term safety and efficacy outcomes

60 months

Treatment Details

Interventions

• RP-A501

Trial Overview The trial is testing RP-A501, a gene therapy delivered via a virus vector designed to introduce a healthy version of the LAMP2B gene into patients' cells. It aims to assess how effective and safe this treatment is in improving symptoms or halting progression of Danon Disease in males.

Participant Groups

Group I: RP-A501 Experimental Treatment 1 Intervention

One planned dose of RP-A501 in cohorts of subjects with a confirmed diagnosis of Danon Disease.

Who Is Running the Clinical Trial?

Rocket Pharmaceuticals Inc.

Lead Sponsor

Trials

17

Recruited

430+

Findings from Research

AAV-mediated gene therapy using a human codon-optimized GAA gene can promote immune tolerance in a mouse model of Pompe disease, potentially improving treatment outcomes by reducing immune responses that limit efficacy.

The combination of AAV9 constructs targeting both liver and muscle tissues not only enhances enzyme expression but also expands regulatory T-cells, which can prevent allergic reactions to enzyme replacement therapy, suggesting a promising dual approach for treating Pompe disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease. Doerfler, PA., Todd, AG., Clément, N., et al.[2018]

AAV8-PAL gene therapy effectively corrected high phenylalanine levels in both male and female PKU mice, demonstrating long-term efficacy after a single intravenous treatment.

The therapy showed no significant liver injury, indicating a safe approach for potential treatment of phenylketonuria (PKU) in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. Tao, R., Xiao, L., Zhou, L., et al.[2022]

The study demonstrated that using a synthetic AAV vector (Anc80) to deliver a functional copy of the PAH gene in a mouse model of PKU resulted in a significant and lasting reduction of phenylalanine levels, indicating effective restoration of metabolic function.

Administration of the AAV vector was safe, with no serious adverse effects observed even at the highest tested dose, and only minor, transient changes in liver enzymes, suggesting a promising approach for gene therapy in PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. Kaiser, RA., Weber, ND., Trigueros-Motos, L., et al.[2022]

Gene therapy using AAV vectors to deliver the RPE65 gene has been shown to be safe and effective for treating Leber's congenital amaurosis (LCA), with positive effects on retinal and visual function lasting at least 1.5 years in patients.

The treatment did not trigger significant immune responses against the RPE65 protein, indicating that AAV-mediated gene transfer can maintain its therapeutic effects without causing harm to the retinal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Simonelli, F., Maguire, AM., Testa, F., et al.[2022]

Gene therapy using a recombinant adenoviral vector to deliver the human PAH gene effectively normalized phenylalanine levels in PAH-deficient mice within one week, showcasing the potential for treating classical phenylketonuria (PKU).

The study found that achieving only 10-20% of normal PAH enzyme activity in the liver was enough to restore normal serum phenylalanine levels, indicating that even partial restoration of enzyme function could be therapeutically beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Fang, B., Eisensmith, RC., Li, XH., et al.[2012]

References

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

Gene Therapy for Pompe Disease: The Time is now. [2020]

2. China pubmed.ncbi.nlm.nih.gov

[Preliminary studies on gene therapy for lysosomal alpha-mannosidosis]. [2012]

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

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease. [2018]

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

Long-term enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vector-mediated gene transfer. [2013]

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

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. [2022]

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

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. [2022]

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

Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. [2022]

8. China pubmed.ncbi.nlm.nih.gov

Enhanced genome editing to ameliorate a genetic metabolic liver disease through co-delivery of adeno-associated virus receptor. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Cas9/sgRNA selective targeting of the P23H Rhodopsin mutant allele for treating retinitis pigmentosa by intravitreal AAV9.PHP.B-based delivery. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. [2012]

11. England pubmed.ncbi.nlm.nih.gov

Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. [2018]