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

Trial Summary

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.

What data supports the effectiveness of the treatment HG004 for Leber Congenital Amaurosis?

Research shows that gene therapy for Leber Congenital Amaurosis, a type of childhood blindness, has been safe and effective in improving vision, although the improvement may decrease over time. This suggests that similar gene therapies, like HG004, could potentially be effective for this condition. ^{1 2 3 4 5}

Is gene therapy for Leber Congenital Amaurosis safe?

Gene therapy for Leber Congenital Amaurosis has been shown to be generally safe in humans, with studies indicating no significant harmful immune responses and stable improvements in vision for at least 1.5 years after treatment. ^{1 3 4 6 7}

How does the treatment HG004 for Leber Congenital Amaurosis differ from other treatments?

HG004 is a gene therapy that uses a viral vector to deliver a healthy copy of a gene to the retina, which is different from traditional treatments that may not address the genetic cause of the condition. This approach is unique because it targets the underlying genetic mutations causing the disease, potentially offering a more effective and long-lasting solution. ^{1 2 3 5 8}

What is the purpose of this trial?

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 mutations in RPE65 gene.

Research Team

Study Director

Principal Investigator

HuidaGene Therapeutics Co., Ltd.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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]

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]

References

1. 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]

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

Improvement and decline in vision with gene therapy in childhood blindness. [2022]

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

Defining Outcomes for Clinical Trials of Leber Congenital Amaurosis Caused by GUCY2D Mutations. [2017]

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

Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups. [2023]

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

Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. [2022]

8. China pubmed.ncbi.nlm.nih.gov

[Progress in gene therapy study of Leber congenital amaurosis]. [2012]