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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy called voretigene neparvovec-rzyl to improve vision in people with Leber Congenital Amaurosis, a rare genetic eye disorder. The treatment targets the eye not treated in an earlier study to determine if it can safely improve or restore vision. Suitable participants have already taken part in a previous study with this treatment and retain some vision in the untreated eye. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that voretigene neparvovec-rzyl is likely to be safe for humans?

Research has shown that voretigene neparvovec-rzyl, a type of gene therapy, is generally well-tolerated. In earlier tests, individuals with Leber Congenital Amaurosis (LCA), a rare eye disorder, received this treatment. These studies focused on safety and found it safe for most participants.

Reports from real-world use also support these findings, indicating that even young patients handled the treatment well. While some side effects occurred, they were mostly mild and manageable.

Interestingly, the FDA has already approved this therapy for treating LCA, further supporting its safety. This approval means the treatment is considered safe enough for use outside clinical trials. Overall, the available data reassures those considering joining a trial for this treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Leber Congenital Amaurosis, which primarily involve supportive care and vitamin A supplementation, voretigene neparvovec-rzyl offers a groundbreaking approach by using gene therapy. This treatment directly targets the genetic root of the condition by delivering a normal copy of the RPE65 gene to retinal cells, which is intended to restore vision. Researchers are particularly excited because this method not only addresses the cause of vision loss but also has the potential to offer long-lasting improvements after just a single administration.

What evidence suggests that voretigene neparvovec-rzyl might be an effective treatment for Leber Congenital Amaurosis?

Research has shown that voretigene neparvovec-rzyl, the treatment under study in this trial, can improve vision for people with Leber Congenital Amaurosis due to RPE65 gene mutations. One study found that patients navigated better in low-light conditions after treatment. Another report noted improved vision in dim light due to enhanced retinal sensitivity. Approved in 2017, this gene therapy works by replacing the faulty RPE65 gene with a healthy one to help restore vision. Safety data from various studies indicate that it is generally well-tolerated. ^{2 3 4 5 6}

Who Is on the Research Team?

Clinical Director

Principal Investigator

Spark Therapeutics, Inc.

Are You a Good Fit for This Trial?

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.

Willingness to adhere to protocol and long-term follow-up as evidenced by written informed consent or parental permission and subject assent (where applicable)

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9010358/

Real-world Outcomes of Voretigene Neparvovec Treatment in ... Voretigene neparvovec-rzyl, approved by the US Food and Drug Administration in 2017 as the first-ever in vivo durable targeted gene therapy for RPE65-associated ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00999609

NCT00999609 | Safety and Efficacy Study in Subjects With ... The purpose of this research study is to assess the efficacy and safety of the AAV2-hRPE65v2 gene therapy vector (voretigene neparvovec-rzyl) as a possible ...

3. canadianjournalofophthalmology.ca canadianjournalofophthalmology.ca/article/S0008-4182(24)00374-0/fulltext

Insights into the effects of subretinal voretigene neparvovec ... Following a safe gene replacement therapy, the 3 first Canadian cases had an improvement in retinal sensitivity as per FST, and our patients ...

4. ophthalmologyscience.org ophthalmologyscience.org/article/S2666-9145(25)00174-5/fulltext

Efficacy and Safety of Voretigene Neparvovec in RPE65- ... We report the efficacy and safety of voretigene neparvovec (VN) as an adeno-associated viral vector–based gene therapy for Japanese patients with inherited ...

5. clinicaltrial.be clinicaltrial.be/en/details/13280?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Safety and Efficacy Study in Subjects With Leber Congenit... The purpose of this research study is to assess the efficacy and safety of the AAV2-hRPE65v2 gene therapy vector (voretigene neparvovec-rzyl) as ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00516477

Safety Study in Subjects With Leber Congenital Amaurosis The primary objective of this study is to determine the safety and tolerability of subretinal administration of AAV2-hRPE65v2 to subjects with LCA due to ...