Gene Therapy for Leber Congenital Amaurosis

(STAR Trial)

Recruiting at 2 trial locations

Overseen By Study Director

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: HuidaGene Therapeutics Co., Ltd.

Disqualifiers: Glaucoma, Epiretinal membrane, Prior surgery, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8-12 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy called HG004 to determine its safety and effectiveness in treating Leber Congenital Amaurosis, a rare eye condition that can cause vision loss due to specific genetic mutations. The therapy targets mutations in the RPE65 gene, which affects light processing in the eye. Suitable candidates for this trial include those diagnosed with Leber Congenital Amaurosis due to RPE65 mutations and who experience significant vision problems, such as difficulty seeing clearly or a limited field of vision. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in gene therapy.

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

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that HG004 is likely to be safe for humans?

Research has shown that HG004, a gene therapy for Leber Congenital Amaurosis, is generally safe and well-tolerated. In earlier studies, most patients did not experience any serious side effects. Specifically, 60% of patients reported improved vision, with no serious problems noted. Many side effects were mild and related to the treatment process itself. This suggests that HG004 is safe for humans based on the current data. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Leber Congenital Amaurosis, which mainly focus on managing symptoms or slowing disease progression, HG004 is a gene therapy that aims to address the root cause of the condition by targeting the genetic mutation responsible. This innovative approach involves delivering a functional copy of the gene directly to the eye's retinal cells, potentially restoring vision or halting further vision loss. Researchers are excited about HG004 because it offers the possibility of a one-time treatment with long-lasting effects, which could be a game-changer for patients who currently have limited therapeutic options.

What evidence suggests that HG004 might be an effective treatment for Leber Congenital Amaurosis?

Research has shown that HG004 gene therapy, which trial participants will receive, could help treat Leber Congenital Amaurosis, especially for those with changes in the RPE65 gene. In earlier studies, 60% of patients improved their vision, gaining almost 15 letters on a vision test within six months. This suggests HG004 can significantly enhance visual clarity. No serious side effects emerged, indicating it is likely safe. Overall, these results suggest HG004 could effectively improve vision for patients with this condition. ^{1 2 3 5 6}

Who Is on the Research Team?

Study Director

Principal Investigator

HuidaGene Therapeutics Co., Ltd.

Are You a Good Fit for This Trial?

This trial is for individuals aged 6-50 with Leber Congenital Amaurosis due to RPE65 mutations, who can perform visual tests and have a visual acuity of ≤ 20/80 or field less than 20 degrees. They must have normal blood, chemistry, and urine lab results. Those with certain pre-existing eye conditions, recent eye surgery, prior gene therapy, or diseases affecting ocular function cannot participate.

Inclusion Criteria

I am between 6 and 50 years old.

Your vision in the eye receiving the injection is very poor, with a visual acuity of 20/80 or a visual field less than 20 degrees.

I can perform tests for eye and vision health.

Exclusion Criteria

I have not had eye surgery in the last 6 months.

I do not have eye conditions that would affect surgery or study results.

I have not had gene or oligonucleotide therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive HG004 gene therapy to evaluate safety and efficacy

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• HG004

Trial Overview The STAR trial is testing the safety and effectiveness of HG004 as a gene therapy for treating blindness caused by specific genetic mutations in patients with Leber Congenital Amaurosis. The focus is on whether this treatment can improve vision in affected individuals.

How Is the Trial Designed?

Group I: HG004 Experimental Treatment 1 Intervention

HG004 is already approved in United States, China for the following indications:

Approved in United States as HG004 for:

• Leber Congenital Amaurosis caused by mutations in RPE65 gene

Approved in China as HG004 for:

• Leber Congenital Amaurosis caused by mutations in RPE65 gene

Who Is Running the Clinical Trial?

HuidaGene Therapeutics Co., Ltd.

Lead Sponsor

Trials

8

Recruited

80+

Cholgene Therapeutics, Inc.

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

The gene therapy for G11778A Leber hereditary optic neuropathy (LHON) demonstrated a favorable safety profile, with the only significant adverse event being uveitis, which occurred in 29% of participants but did not lead to lasting vision problems.

While some patients showed improvements in visual acuity, the overall efficacy of the treatment appears to be small and not related to the dose, indicating that further randomized studies are needed to confirm any potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups. Lam, BL., Feuer, WJ., Davis, JL., et al.[2023]

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]

Retinal gene therapy for Leber's congenital amaurosis has shown initial safety and efficacy, with vision improvements maintained for up to 6 years in some patients.

However, long-term follow-up revealed that while vision improvements were sustained, the rate of photoreceptor loss in treated retinas was similar to that in untreated retinas, indicating a potential limitation in the therapy's long-term effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement and decline in vision with gene therapy in childhood blindness. Jacobson, SG., Cideciyan, AV., Roman, AJ., et al.[2022]

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]

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]

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]

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 study of 28 patients with GUCY2D-associated Leber congenital amaurosis, various testing methods like full-field sensitivity testing (FST) and optical coherence tomography (OCT) were used to assess visual function and retinal structure, revealing significant losses in rod and cone sensitivity and structural abnormalities.

The findings suggest that traditional outcome measures like visual acuity may not be sufficient for this condition, highlighting the need for specific assessments of rod and cone function and structure to evaluate the efficacy of potential therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defining Outcomes for Clinical Trials of Leber Congenital Amaurosis Caused by GUCY2D Mutations. Jacobson, SG., Cideciyan, AV., Sumaroka, A., et al.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2839440/

Gene Therapy for Leber's Congenital Amaurosis is Safe and ... Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration - PMC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06088992

Leber Congenital Amaurosis Inherited Blindness of Gene ... The purpose of the study is to determine whether HG004 as gene therapy is safe and effective for the treatment of Leber Congenital Amaurosis caused by ...

3. iovs.arvojournals.org iovs.arvojournals.org/article.aspx?articleid=2798148

HG004 Gene Therapy for Patients with Leber Congenital ... 60% of evaluable patients in these doses reached nearly 15 (14-18) letters of BCVA improvement at either 6- or 3-month visits. No serious adverse event or dose- ...

4. fightingblindness.org fightingblindness.org/news/leber-congenital-amaurosis-research-advances-861

Leber Congenital Amaurosis Research Advances MeiraGTx, a genetic medicines company in New York and London, has reported significant vision improvements for 11 children, between the ages of one and four, ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa0802315

Safety and Efficacy of Gene Transfer for Leber's Congenital ... Most patients with LCA have severe visual impairment throughout childhood; vision deteriorates over time, and patients usually have total blindness by the third ...

6. aao.org aao.org/eyenet/article/leber-congenital-amaurosis-therapy

Small Trial Tests Drug Safety in People With LCA The gene therapy was generally safe and well tolerated among all participants and most of the documented side effects were attributed to the ...