Gene Therapy for Leber Congenital Amaurosis

(LCA Trial)

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Anti-platelet, Immunosuppressive

Disqualifiers: Pregnancy, Eye conditions, Systemic diseases, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop using anti-platelet agents (medications that prevent blood clots) within 7 days before receiving the study treatment. It also excludes those using immunosuppressive medications. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment rAAV2-CBSB-hRPE65 for Leber Congenital Amaurosis?

Research shows that gene therapy using a similar approach with rAAV2 carrying the RPE65 gene has been effective in improving vision in patients with Leber congenital amaurosis caused by RPE65 mutations, with some improvements in photoreceptor function observed in both animal models and humans. ^{1 2 3 4 5}

Is gene therapy for Leber Congenital Amaurosis using rAAV2-CBSB-hRPE65 safe?

Gene therapy using rAAV2-CBSB-hRPE65 for Leber Congenital Amaurosis has been shown to be safe in humans, with no serious side effects reported up to one year after treatment. Studies in both humans and animals have not found significant immune reactions or systemic toxicities, indicating the treatment is generally safe. ^{2 5 6 7 8}

How is the treatment rAAV2-CBSB-hRPE65 unique for Leber Congenital Amaurosis?

The treatment rAAV2-CBSB-hRPE65 is unique because it uses gene therapy to deliver a healthy copy of the RPE65 gene directly into the retina, aiming to restore vision in patients with Leber Congenital Amaurosis caused by RPE65 mutations. This approach is different from other treatments as it targets the genetic root of the condition, potentially offering a more lasting improvement in vision. ^{1 2 3 4 5}

What is the purpose of this trial?

A recombinant adeno-associated virus serotype 2 (rAAV2) vector has been altered to carry the human RPE65 (hRPE65) gene. This vector has been shown to restore vision in animal models that resemble human RPE65-associated Leber congenital amaurosis (LCA), an incurable retinal degeneration that causes severe vision loss. The proposed study is an open label, Phase I clinical trial of subretinal rAAV2-CBSB-hRPE65 administration to individuals with RPE65-associated retinal disease. Five cohorts will be included in this trial. Cohorts 1, 2 and 4 will consist of individuals 18 years of age and older. Cohorts 3 and 5 will consist of individuals between the ages of 8 and 17, inclusive. Enrollment in Cohorts 3 and 5 will begin only after confirming the safety of rAAV2-CBSB-hRPE65 administration in the older groups of participants. This trial will lead to a greater understanding of the safety and thereby potential value of gene transfer in RPE65-associated retinal disease and will have implications for other forms of retinal degenerative disease amenable to this type of intervention. The goal of this clinical trial is to determine the safety of uniocular subretinal administration of rAAV2-CBSB-hRPE65 in individuals with RPE65-associated retinal disease. Ocular and systemic toxicity will be assessed prior to and following vector administration to determine if there are adverse changes that may be associated with vector administration.

Research Team

Samuel G. Jacobson, MD, PhD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for individuals with RPE65-associated retinal disease, which can lead to severe vision loss. It's open to adults and children (8-17 years after safety confirmation in adults). Participants must have a visible photoreceptor layer on OCT scans, be able to perform visual tests, and comply with research procedures. They should not have complicating diseases or conditions that could interfere with the study.

Inclusion Criteria

I have LCA/EORD with very poor vision in my study eye.

You are in overall good health.

Ability to comply with research procedures

Exclusion Criteria

Your body has a high level of AAV antibodies before starting the study.

I don't have eye conditions that would affect surgery or study results.

Any condition that makes the subject unsuitable for the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Subretinal administration of rAAV2-CBSB-hRPE65 to individuals with RPE65-associated retinal disease

1 day

1 visit (in-person)

Follow-up

Participants are monitored for ocular and systemic toxicity to assess safety of the gene vector

12 months

Multiple visits (in-person)

Treatment Details

Interventions

• rAAV2-CBSB-hRPE65

Trial Overview The trial is testing a gene therapy called rAAV2-CBSB-hRPE65 delivered directly under the retina. The goal is to restore vision in those affected by certain genetic mutations causing retinal disease. This early-phase study will assess safety across different age groups before and after treatment.

Participant Groups

Group I: Experimental Experimental Treatment 1 Intervention

All clinical trial subjects received the same vector.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Eye Institute (NEI)

Collaborator

Trials

572

Recruited

1,320,000+

Findings from Research

Gene augmentation therapy using AAV8-hLCA5 can effectively rescue photoreceptor function and structure in a mouse model of Leber congenital amaurosis (LCA) if administered before postnatal day 30, highlighting a critical therapeutic window.

Patients with LCA5 mutations retain some photoreceptors in the central retina, suggesting that similar gene therapy could be beneficial for them, as their condition mirrors the severe degeneration seen in the mouse model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Potential for LCA5-Associated Leber Congenital Amaurosis. Uyhazi, KE., Aravand, P., Bell, BA., et al.[2021]

Subretinal gene therapy using rAAV2 carrying the RPE65 gene was found to be safe, with no systemic toxicity and only minor ocular adverse events related to the surgical procedure in a study of 15 patients aged 11 to 30.

Visual function improved in all treated patients, particularly in those with the lowest initial acuities, indicating that gene therapy can be effective for restoring vision in specific areas of the retina, although treatment of the fovea may carry risks without benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Jacobson, SG., Cideciyan, AV., Ratnakaram, R., et al.[2022]

Gene therapy using AAV vectors to deliver the AIPL1 gene shows promise for treating Leber congenital amaurosis 4 (LCA4), as it restored AIPL1 expression and protected photoreceptors from degeneration in Aipl1 null mice.

In a study of 10 LCA4 patients, advanced imaging revealed surviving photoreceptors in certain retinal areas, suggesting these regions could be targeted for effective gene therapy, with AAV2/8 delivery demonstrating high expression levels without toxicity in porcine models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Italian patients with leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy. Testa, F., Surace, EM., Rossi, S., et al.[2021]

Human gene therapy using the rAAV2 vector for treating RPE65-related Leber congenital amaurosis was found to be safe, with no serious adverse events reported in young adult subjects up to 12 months after treatment.

Patients showed sustained improvements in visual sensitivity from 3 months to 12 months post-treatment, indicating the long-term efficacy of the gene therapy in enhancing vision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Cideciyan, AV., Hauswirth, WW., Aleman, TS., et al.[2022]

In a study using large animal models, sequential bilateral injections of rAAV2-hRPE65v2 were found to be safe and effective for treating Leber's congenital amaurosis (LCA), even when the second eye was treated after the first injection.

Despite the development of neutralizing antibodies against the AAV2 capsid, the treatment did not trigger significant immune responses, and it resulted in improved visual function with minimal inflammation in affected animals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Amado, D., Mingozzi, F., Hui, D., et al.[2022]

References

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

Treatment Potential for LCA5-Associated Leber Congenital Amaurosis. [2021]

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

Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. [2022]

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

Evaluation of Italian patients with leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65. [2022]

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

Recombinant adeno-associated virus type 2-mediated gene delivery into the Rpe65-/- knockout mouse eye results in limited rescue. [2020]

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

Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. [2022]

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

Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. [2022]

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

Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. [2022]