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

Trial Summary

What is the purpose of this trial?

This trial is testing a new gene therapy injected under the retina to help people with a specific genetic eye condition that causes vision loss. The therapy aims to replace faulty genes with healthy ones to improve vision. Mutations in the RPE65 gene are one of the causes of RP and Leber congenital amaurosis (LCA), a form of RP present at birth.

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.

What data supports the idea that Gene Therapy for Leber Congenital Amaurosis is an effective treatment?

The available research shows that gene therapy for Leber Congenital Amaurosis (LCA) has been successful in improving vision. In animal studies, the therapy was able to deliver a corrective gene to the eye's cells, leading to long-term vision improvement. Clinical trials in humans, particularly for those with LCA type 2, have shown that a single injection of the therapy can reverse blindness and improve visual function. These trials have demonstrated safety and effectiveness, even when the treatment is administered to both eyes. This suggests that gene therapy is a promising treatment for LCA compared to other options. ^{1 2 3 4 5}

What safety data exists for gene therapy in Leber Congenital Amaurosis?

The safety of gene therapy for Leber Congenital Amaurosis (LCA) has been evaluated in various studies. In animal models, subretinal delivery of AAV vectors, such as AAV2.RPE65, was well tolerated with minimal toxicity and improved visual function. In human trials, subretinal administration of AAV2-hRPE65v2 showed safety and efficacy, with improvements in visual and retinal function persisting for at least 1.5 years. A transient rise in neutralizing antibodies to the AAV capsid was observed, but no significant immune response to the transgene product was noted. Additionally, readministration of the vector in large animals was safe, even with preexisting immunity to the vector. These findings support the safety of AAV-mediated gene therapy for LCA. ^{3 4 6 7 8}

Is the treatment AAV8.hLCA5 a promising treatment for Leber Congenital Amaurosis?

Yes, AAV8.hLCA5 is a promising treatment for Leber Congenital Amaurosis because gene therapy has shown success in improving vision in similar conditions, and it offers hope for treating this genetic eye disease. ^{1 2 3 9 10}

Eligibility Criteria

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

I am 18 years old or older.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Gene therapy for Leber congenital amaurosis. [2012]

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

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

3. China pubmed.ncbi.nlm.nih.gov

[Progress in gene therapy study of Leber congenital amaurosis]. [2012]

4. 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]

5. United States 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. [2022]

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

Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. [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. England 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. [2021]

9. 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]

10. 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]