Gene Therapy for Leber Congenital Amaurosis

(LCA Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new gene therapy for individuals with Leber congenital amaurosis (LCA), a condition causing severe vision loss. The treatment, rAAV2-CBSB-hRPE65, uses a modified virus to deliver a healthy gene into the eye, with the goal of improving vision. Participants must have LCA caused by RPE65 gene mutations and significant vision impairment. Those who meet these criteria and can undergo eye tests may find this trial suitable. Understanding the safety of this treatment could also benefit other eye conditions in the future. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

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

Research has shown that the gene therapy treatment, rAAV2-CBSB-hRPE65, has been tested in several studies and appears safe. In earlier trials with individuals who have RPE65-related eye disease, the treatment caused no serious side effects. Importantly, there were no immune reactions, indicating the body did not reject the treatment.

Studies on this gene therapy for eye disease have consistently demonstrated its safety. Some studies even reported improvements in vision, which is encouraging. While each new study enhances understanding of safety, these early results suggest that the treatment is well-tolerated in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Leber Congenital Amaurosis, which typically focus on managing symptoms through visual aids or supportive therapies, rAAV2-CBSB-hRPE65 offers a new approach by targeting the genetic root of the condition. This treatment uses a gene therapy vector to deliver a functional copy of the RPE65 gene directly to retinal cells, addressing the underlying cause rather than just the symptoms. Researchers are excited about this treatment because it has the potential to restore vision, offering a more lasting solution compared to current options.

What evidence suggests that this gene therapy might be an effective treatment for Leber congenital amaurosis?

Research has shown that a new treatment, rAAV2-CBSB-hRPE65, may help with Leber congenital amaurosis (LCA), a serious eye condition that causes vision loss. In animal studies, this gene therapy restored sight, suggesting it might work similarly in people. Early results from patients in this trial, where all participants receive the same vector, indicate that injecting this treatment under the retina can improve vision without causing harmful immune reactions. Studies also found that these vision improvements can last for at least a year after treatment. This supports the potential of rAAV2-CBSB-hRPE65 to treat LCA caused by RPE65 gene mutations. ^{1 3 4 5 6}

Who Is on the Research Team?

Samuel G. Jacobson, MD, PhD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4561397/

The Status of RPE65 Gene Therapy Trials: Safety and Efficacy Several groups have reported the results of clinical trials of gene augmentation therapy for Leber congenital amaurosis (LCA) because of mutations in the RPE65 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2829287/

Human RPE65 Gene Therapy for Leber Congenital Amaurosis The safety and efficacy of human retinal gene transfer with rAAV2-RPE65 vector extends to at least 1 year posttreatment.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00481546

NCT00481546 | Phase I Trial of Gene Vector to Patients ... The proposed study is an open label, Phase I clinical trial of subretinal rAAV2-CBSB-hRPE65 administration to individuals with RPE65-associated retinal disease.

4. aao.org aao.org/education/disease-review/leber-congenital-amaurosis-4

Leber Congenital Amaurosis Leber congenital amaurosis (LCA) manifests itself in the first 6 months of life with significant visual loss and sensory, pendular nystagmus ...

5. access.portico.org access.portico.org/Portico/show?viewFile=pdf&auId=pjbf78x6665

rAAV2-CBSB-hRPE65 Preliminary results indicate that subretinal injection of rAAV2-CBSB-hRPE65 does not produce any discernable adverse immunogenic response and can improve visu-.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/18774912/

Treatment of leber congenital amaurosis due to RPE65 ... A clinical trial was designed to assess the safety of rAAV2-CBSB-hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21-24 years) with RPE65-LCA ...