Gene Therapy for Leber Congenital Amaurosis

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Spark Therapeutics, Inc.

Must not be taking: Retinoid compounds

Disqualifiers: Glaucoma, Diabetes, Sickle cell, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The study is a follow-on to a Phase 1 dose-escalation and safety study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use retinoid compounds or precursors. If you stop using these compounds for 18 months, you may become eligible to participate.

What data supports the effectiveness of the treatment voretigene neparvovec-rzyl for Leber Congenital Amaurosis?

Research shows that voretigene neparvovec-rzyl improves vision in children with Leber Congenital Amaurosis, with some achieving full visual acuity and partial recovery of eye function that was previously undetectable. ^{1 2 3 4 5}

Is voretigene neparvovec-rzyl safe for humans?

Voretigene neparvovec-rzyl has been used in gene therapy for Leber Congenital Amaurosis, and while it generally improves vision, some patients have experienced changes in the eye, such as chorioretinal atrophy (thinning of the retina and choroid). This suggests that while the treatment can be effective, there may be some risks involved. ^{1 4 5 6 7}

What makes the treatment voretigene neparvovec-rzyl unique for Leber Congenital Amaurosis?

Voretigene neparvovec-rzyl is unique because it is the first approved gene therapy specifically designed to treat Leber Congenital Amaurosis caused by mutations in the RPE65 gene, offering a causative treatment option that can improve vision and partially restore eye function in affected individuals. ^{1 3 4 5 8}

Research Team

Clinical Director

Principal Investigator

Spark Therapeutics, Inc.

Eligibility Criteria

This trial is for individuals with Leber Congenital Amaurosis who have participated in a prior Phase 1 study and received treatment in one eye. They must have some visual acuity, viable retinal cells in the other eye, and be willing to follow long-term protocols. Pregnant individuals or those not using effective contraception are excluded, as well as anyone with conditions that could affect the study's outcome.

Inclusion Criteria

I have previously been in a study where I received a specific gene therapy in one eye.

You can see light or have better vision.

My other eye has enough healthy retina cells, confirmed by eye scans.

Exclusion Criteria

I do not have eye conditions or systemic diseases that could affect my eyes or interfere with the surgery.

My gender, race, or ethnicity does not affect my eligibility.

Any other condition that would not allow the potential subject to complete follow-up examinations during the course of the study and, in the opinion of the investigator, makes the potential subject unsuitable for the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Administration of AAV2-hRPE65v2 vector to the previously uninjected contralateral eye

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• voretigene neparvovec-rzyl

Trial Overview The trial is testing voretigene neparvovec-rzyl, a gene therapy previously administered to one eye of participants. Now it will be given to their other eye which hasn't been treated yet. The focus is on safety following this second administration.

Participant Groups

Group I: voretigene neparvovec-rzyl (AAV2-hRPE65v2) Experimental Treatment 1 Intervention

Administration of study agent (AAV2-hRPE65v2) to the previously, uninjected contralateral eye:

Who Is Running the Clinical Trial?

Spark Therapeutics, Inc.

Lead Sponsor

Trials

16

Recruited

410+

Spark Therapeutics

Lead Sponsor

Trials

14

Recruited

350+

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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Gene Therapy with Voretigene Neparvovec Improves Vision and Partially Restores Electrophysiological Function in Pre-School Children with Leber Congenital Amaurosis. [2023]

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

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

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

Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence. [2023]

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

Perifoveal Chorioretinal Atrophy after Subretinal Voretigene Neparvovec-rzyl for RPE65-Mediated Leber Congenital Amaurosis. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Multi-luminance mobility testing after gene therapy in the context of retinal functional diagnostics. [2023]

7. Hungary pubmed.ncbi.nlm.nih.gov

[Gene therapy treatment based on an ophthalmic indication in hereditary retinal dystrophy caused by RPE65 biallelic gene mutation.] [2022]

8. 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]