Gene Therapy for Leber Congenital Amaurosis

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

31 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment AAV2-hRPE65v2, voretigene neparvovec-rzyl for Leber Congenital Amaurosis?

Research shows that voretigene neparvovec, a gene therapy, improves vision in children with Leber congenital amaurosis caused by RPE65 mutations. In studies, children treated with this therapy showed significant improvements in vision-guided behavior and visual acuity, with some experiencing partial recovery of retinal function. ^{1 2 3 4 5}

Is gene therapy with voretigene neparvovec safe for humans?

Gene therapy with voretigene neparvovec has been generally well tolerated in humans, with studies showing good eye and overall tolerance in patients with Leber congenital amaurosis. In animal studies, the treatment was also well tolerated, showing minimal toxicity to the retina. ^{3 6 7 8 9}

How is 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 retinal dystrophies caused by RPE65 mutations, offering a causative treatment option for this condition. It involves a subretinal injection that delivers a functional copy of the RPE65 gene, which can improve vision and partially restore retinal function in affected individuals. ^{3 4 5 10 11}

What is the purpose of this trial?

The study is a Phase 3, open-label, randomized controlled trial of gene therapy intervention by subretinal administration of AAV2-hRPE65v2 (voretigene neparvovec-rzyl). At least twenty-four subjects, three years of age or older, will be recruited. The intervention group will receive AAV2-hRPE65v2 at either The Children's Hospital of Philadelphia or University of Iowa to determine if it improves visual and retinal function in individuals with RPE65 gene mutations.

Research Team

Stephen R Russell, MD

Principal Investigator

University of Iowa

Albert M Maguire, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

References

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

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

2. 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]

3. 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]

4. 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]

5. United States 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. [2021]

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

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

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

Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis. [2022]

8. 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]

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

Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. [2022]

10. 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]

11. England pubmed.ncbi.nlm.nih.gov

Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65. [2022]