Gene Therapy for Leber Congenital Amaurosis

Not currently recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Spark Therapeutics, Inc.

Must not be taking: Retinoid compounds

Disqualifiers: Gene therapy, Investigational drug, Eye surgery, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 2-3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy treatment, AAV2-hRPE65v2 (also known as voretigene neparvovec-rzyl), to determine if it can improve vision in individuals with Leber Congenital Amaurosis (LCA) caused by RPE65 gene mutations. Participants will receive the experimental treatment through an injection into the eye to assess its impact on sight and eye function. The trial seeks individuals diagnosed with LCA who have specific vision difficulties and meet other criteria related to eye health. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for LCA.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop all current medications, but you must stop using retinoid compounds or precursors for 18 months before participating. It's best to discuss your specific medications with the trial team.

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

Research has shown that voretigene neparvovec-rzyl has been tested for safety and effectiveness in people with certain genetic eye conditions. In these studies, researchers administered this gene therapy to evaluate its efficacy and safety. Most participants tolerated it well, experiencing no major side effects.

One study found that some patients experienced temporary issues like eye inflammation or increased eye pressure, but these were manageable. No severe or lasting problems were reported. The treatment's progression to a later stage of testing suggests that earlier tests demonstrated its relative safety.

Additionally, the FDA has already approved this therapy for another eye-related condition, further supporting its safety record. For those considering joining a clinical trial, this information might be reassuring. Discussing any concerns with a healthcare provider is always advisable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for Leber Congenital Amaurosis, which primarily involves supportive therapies like low vision aids and vitamin A supplements, voretigene neparvovec-rzyl offers a groundbreaking approach through gene therapy. This treatment is unique because it uses a viral vector, AAV2-hRPE65v2, to deliver a correct copy of the RPE65 gene directly to the retina via subretinal injection. This innovative mechanism has the potential to restore vision by targeting the underlying genetic cause of the condition, rather than just managing symptoms. Researchers are excited about this treatment because it represents a one-time intervention that could provide long-lasting improvements in vision.

What evidence suggests that this gene therapy could be effective for Leber Congenital Amaurosis?

Research has shown that voretigene neparvovec, a type of gene therapy, offers promising results for treating Leber congenital amaurosis, a vision disorder caused by RPE65 gene mutations. In this trial, some participants will receive voretigene neparvovec. Studies have found that patients who received this treatment experienced significant improvements in vision and eye function. One study demonstrated that these improvements lasted for at least 1.5 years. Real-world evidence also supports these findings, indicating that the therapy can enhance vision in children. This treatment addresses the genetic cause of the condition, which is why it is expected to be effective. ^{1 2 3 5 6}

Who Is on the Research Team?

Stephen R Russell, MD

Principal Investigator

University of Iowa

Albert M Maguire, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for individuals aged three or older with Leber Congenital Amaurosis (LCA) due to RPE65 mutations, confirmed by a lab. Participants must have poor vision but enough viable retinal cells and be able to perform mobility tests. Pregnant individuals or those not using contraception, with prior gene therapy, recent investigational drug use, or conditions affecting the study's outcome cannot join.

Inclusion Criteria

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

You have enough healthy cells in your eyes, as checked by non-invasive tests like optical coherence tomography (OCT) and ophthalmoscopy.

I am at least three years old.

Exclusion Criteria

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

Participation in a clinical study with an investigational drug in the past six months

I don't have eye conditions or other illnesses that would affect surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive subretinal injections of AAV2-hRPE65v2 in both eyes, 6-18 days apart

2-3 weeks

2 surgical visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments like MLMT and FST

1 year

Regular follow-up visits (in-person)

Crossover

Control group participants may cross over to receive the intervention after one year if eligibility criteria are met

1 year

What Are the Treatments Tested in This Trial?

Interventions

• AAV2-hRPE65v2,voretigene neparvovec-rzyl

Trial Overview The trial studies the safety and effectiveness of a gene therapy called AAV2-hRPE65v2 (voretigene neparvovec-rzyl). It's given as an injection into the eye to see if it can improve sight in people with specific genetic changes causing LCA. The treatment will be administered at select hospitals.

How Is the Trial Designed?

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

voretigene neparvovec rzyl, 1.5 E11 vector genomes, per eye, administered by subretinal injection in a volume of 0.3mL, 6-18 days apart

Group II: Control Active Control 1 Intervention

No intervention

Who Is Running the Clinical Trial?

Spark Therapeutics, Inc.

Lead Sponsor

Trials

16

Recruited

410+

Spark Therapeutics

Lead Sponsor

Trials

14

Recruited

350+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

Published Research Related to This Trial

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 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]

Subretinal gene therapy using the AAV2-CB(SB)-hRPE65 vector in RPE65-deficient rd12 mice showed improved retinal function, with significant increases in b-wave amplitudes and faster photoresponse kinetics at certain doses, indicating therapeutic efficacy.

The study established a full-field electroretinogram (ERG) assay to measure the biological activity of the gene therapy vector, which could be useful for evaluating future clinical trials in humans with RPE65-related retinal diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Roman, AJ., Boye, SL., Aleman, TS., 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]

Citations

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

Real-world Outcomes of Voretigene Neparvovec Treatment in ... Real-world outcomes data of RPE65-associated Leber congenital amaurosis in pediatric patients treated with subretinal voretigene neparvovec show significant ...

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

Efficacy and Safety of Voretigene Neparvovec in RPE65- ... RPE65-retinopathy accounts for 5% to 10% of all Leber congenital amaurosis or early-onset severe retinal dystrophy cases and 0.4% to 1.2% of all IRD cases.

4. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(17)31868-8/abstract

a randomised, controlled, open-label, phase 3 trial Simonelli, F ∙ Maguire, AM ∙ Testa, F ∙ et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1·5 years after vector administration.

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

Insights into the effects of subretinal voretigene neparvovec ... Data collected included demographic information, molecular genetic results, and comprehensive ocular assessment results from preoperataive ...

6. 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 ...