Gene Therapy for Leber Congenital Amaurosis

Overseen By Jasminder Soto

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Opus Genetics, Inc

Must not be taking: Investigational drugs

Disqualifiers: Pregnancy, Immunocompromised, Recent eye surgery, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a gene therapy treatment aimed at improving vision for individuals with inherited retinal degeneration caused by mutations in the LCA5 gene. Researchers are testing the safety and initial effectiveness of the treatment, OPGx-001 (also known as AAV8.hLCA5), delivered as a subretinal injection. Participants suitable for this trial have been diagnosed with Leber Congenital Amaurosis due to LCA5 mutations and experience significant vision impairment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have used any investigational drug or device within 90 days before the trial. It's best to discuss your current medications with the trial investigator.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the gene therapy OPGx-001 has been safe for patients so far. In earlier studies, the treatment did not cause any surgery- or drug-related problems or unexpected side effects. This indicates that recipients did not experience surprising or serious issues due to the treatment.

Patients in these studies returned to their usual vision levels after treatment, without any new problems. This suggests that OPGx-001 is likely safe for treating Leber Congenital Amaurosis. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Leber Congenital Amaurosis?

Researchers are excited about AAV8.hLCA5 for Leber Congenital Amaurosis (LCA) because it offers a novel approach compared to current treatments, which mainly include supportive measures like low-vision aids or vitamin A supplementation. AAV8.hLCA5 uses gene therapy to directly target the genetic root of the condition by delivering a healthy copy of the LCA5 gene to retinal cells. This method aims to restore vision by fixing the underlying genetic defect, rather than just managing symptoms. Additionally, the treatment is delivered through a single subretinal injection, which is less invasive and potentially more effective than repeated procedures or systemic treatments.

What evidence suggests that this trial's treatments could be effective for Leber Congenital Amaurosis?

Research has shown that the gene therapy OPGx-001 could help treat Leber Congenital Amaurosis type 5 (LCA5), a rare eye condition. In earlier studies, adults who received this treatment experienced lasting improvements in their ability to see light and overall vision for up to 18 months. Teenagers also showed significant improvements in their vision. Importantly, the therapy proved safe, with no serious side effects reported. In this trial, participants will receive different doses of OPGx-001 to further evaluate its safety and effectiveness. These findings suggest that OPGx-001 might improve vision in people with LCA5. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

Adults with inherited retinal degeneration due to LCA5 gene mutations, who have visual acuity less than 20/80 and detectable photoreceptors. Candidates must be able to undergo surgery, follow post-surgery instructions, use effective contraception if of childbearing potential, and commit to the study protocol.

Inclusion Criteria

Visual acuity: BCVA < 20/80 on the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart (modified for low vision participants) in the eye to be treated

Are willing and able to provide written informed consent (ICF) and, where appropriate, willing to sign an assent prior to any study procedures

Show evidence of detectable photoreceptors by Spectral Domain Optical Coherence Tomography (SD-OCT)

Exclusion Criteria

I cannot take oral steroids for medical reasons.

I haven't used any experimental drugs or devices recently and don't plan to join another study soon.

I haven't had eye surgery in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single, unilateral subretinal injection of OPGx-001 at varying doses across three cohorts, with a 30-day safety evaluation and data committee review after each dose

3 months

Multiple visits for dosing and safety evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment, with primary and secondary outcome measures assessed over a 1-year period

12 months

Regular visits for outcome assessments

What Are the Treatments Tested in This Trial?

Interventions

• AAV8.hLCA5

Trial Overview The trial is testing a subretinal gene therapy called OPGx-001 for safety and initial effectiveness in treating vision loss caused by LCA5-associated retinal degeneration. It involves surgical delivery of the AAV8.hLCA5 gene therapy directly into the retina.

How Is the Trial Designed?

Group I: Dose Group 3 Experimental Treatment 1 Intervention

A single, unilateral, subretinal injection of high dose (1E11 vg/eye) OPGx-001 is injected into two LCA5 adults (18 yo or above) in a sentinel fashion. A 30-day safety evaluation and data committee review and approval of continued dosing occurs. If additional dosing is recommended, a subsequent LCA5 adolescent (13-17) may be treated in a sentinel fashion, with a unilateral, subretinal injection of OPGx-001. A 30-day safety evaluation and data committee review and approval of continued dosing occurs. If additional dosing is recommended, two remaining adolescents (13-17) are eligible to be treated with a single, unilateral, subretinal injection of a high dose of OPGx-001. Total cohort size is 5 (2 adults and 3 adolescents).

Group II: Dose Group 2 Experimental Treatment 1 Intervention

A single, unilateral, subretinal injection of an intermediate dose (3E10 vg/eye) OPGx-001 is injected into two LCA5 adults (18 yo or above) in a sentinel fashion. A 30-day safety evaluation and data committee review and approval of continued dosing occurs. If additional dosing is recommended, a subsequent LCA5 adolescent (13-17) may be treated in a sentinel fashion, with a unilateral, subretinal injection of OPGx-001. A 30-day safety evaluation and data committee review and approval of continued dosing occurs. If additional dosing is recommended, two remaining adolescents (13-17) are eligible to be treated with a single, unilateral, subretinal injection of an intermediate dose of OPGx-001. Total cohort size is 5 (2 adults and 3 adolescents).

Group III: Dose Group 1 Experimental Treatment 1 Intervention

A single, unilateral, subretinal injection of low dose (1E10 vg/eye) OPGx-001 is injected into two LCA5 adults (18 yo or above) in a sentinel fashion. A 30-day safety evaluation and data committee review and approval of continued dosing occurs. If additional dosing is recommended, a subsequent LCA5 adolescent (13-17) may be treated in a sentinel fashion, with a unilateral, subretinal injection of OPGx-001. A 30-day safety evaluation and data committee review and approval of continued dosing occurs. If additional dosing is recommended, two remaining adolescents (13-17) are eligible to be treated with a single, unilateral, subretinal injection of a low dose of OPGx-001. Total cohort size is 5 (2 adults and 3 adolescents).

AAV8.hLCA5 is already approved in United States for the following indications:

Approved in United States as OPGx-LCA5 for:

• Leber congenital amaurosis 5 (LCA5)

Who Is Running the Clinical Trial?

Opus Genetics, Inc

Lead Sponsor

Trials

1

Recruited

20+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

FDA Office of Orphan Products Development

Collaborator

Trials

73

Recruited

6,400+

Published Research Related to This Trial

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 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]

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]

In a mouse model of Leber congenital amaurosis (LCA) caused by Aipl1 gene defects, the novel self-complementary Y733F capsid mutant AAV2/8 (sc-Y733F-AAV) significantly preserved photoreceptors and functional vision compared to traditional single-stranded AAV2/8.

The sc-Y733F-AAV treatment was most effective when administered during the active phase of retinal degeneration, leading to earlier and higher expression of the Aipl1 gene, suggesting it could be a promising approach for future gene therapy trials targeting inherited retinal diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis. Ku, CA., Chiodo, VA., Boye, SL., et al.[2021]

Adeno-associated viral (AAV) vector-mediated gene therapy for Leber congenital amaurosis (LCA) has shown promising results, particularly with the successful Phase I clinical trials for RPE65 gene therapy, marking a significant advancement in retinal gene therapy.

The progress in gene therapy for LCA not only highlights its potential effectiveness in treating this specific condition but also opens up possibilities for curing other hereditary retinal diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Progress in gene therapy study of Leber congenital amaurosis]. Pan, SS., Zheng, QX., Li, WS., et al.[2012]

Adeno-associated virus serotype 2 (AAV2) has successfully delivered a corrective gene to retinal cells in a canine model of Leber congenital amaurosis (LCA), leading to long-term vision rescue.

The positive outcomes from these studies suggest promising implications for future human clinical trials targeting LCA and other retinal degenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for Leber congenital amaurosis. Bennett, J.[2012]

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]

The optimized adeno-associated virus (AAV2.RPE65) demonstrated significant safety and efficacy in animal models of Leber congenital amaurosis (LCA), showing improved visual function and minimal toxicity after subretinal delivery.

In treated Rpe65 mutant mice and dogs, the therapy led to enhanced electroretinogram responses and visual behaviors, indicating effective transduction of retinal pigment epithelium cells and a potential new treatment for LCA caused by RPE65 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Bennicelli, J., Wright, JF., Komaromy, A., et al.[2022]

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]

In a clinical trial involving 5 patients with Leber congenital amaurosis type 2, a single injection of the gene therapy AAV2-hRPE65v2 led to significant and stable improvements in best-corrected visual acuity over a 3-year follow-up period (P<0.001).

All patients showed an increase in their visual field area and a reduction in nystagmus frequency, with no serious adverse events reported, indicating the treatment's safety and long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Testa, F., Maguire, AM., Rossi, S., et al.[2022]

Citations

1. iovs.arvojournals.org iovs.arvojournals.org/article.aspx?articleid=2798147

AAV8-hLCA5 Subretinal Delivery to the Macula in LCA5 ... Results : OPGx-001 was well tolerated to date with no surgery- or drug-related complications or unanticipated adverse events. VA returned to baseline or ...

2. ir.opusgtx.com ir.opusgtx.com/press-releases/detail/501/opus-genetics-reports-positive-pediatric-data-from-opgx-lca5-phase-12-trial-in-leber-congenital-amaurosis-type-5-lca5

Opus Genetics Reports Positive Pediatric Data from OPGx ... The adult cohort showed durable improvements in cone sensitivity and visual function out to 18 months. OPGx-LCA5 has received Rare Pediatric ...

3. ophthalmologytimes.com ophthalmologytimes.com/view/positive-pediatric-data-emerge-from-the-opgx-lca5-phase-1-2-trial-of-leber-congenital-amaurosis-type-5

Positive pediatric data emerge from the OPGx-LCA5 phase ... The key findings of the trial, according to the company, showed: significant measurable gains in vision in teenagers.

4. fightingblindness.org fightingblindness.org/news/opus-reports-vision-improvements-for-three-pediatric-patients-in-phase-1-2-clinical-trial-for-lca5-gene-therapy-2917

Opus Reports Vision Improvements for Three Pediatric ... Durable vision improvements were also observed out to 18 months for previously dosed adult patients in the trial.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40598770/

Recovery of cone-mediated vision in Lebercilin associated ... There were no serious adverse events related to OPGx-001 or the procedure. Retinal microstructure by spectral-domain optical coherence ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1525001625004861

Recovery of Cone-Mediated Vision in Lebercilin ... We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated ...