Gene Therapy for Retinitis Pigmentosa

(HORIZON Trial)

Not currently recruiting at 7 trial locations

Overseen By Jill Dolgin, PharmD

Age: < 65

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Beacon Therapeutics

Must not be taking: Anti-coagulants, Corticosteroids

Disqualifiers: Glaucoma, Diabetic retinopathy, others

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

Compensation: Varies

Number of Visits: 19

Duration: 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy for X-linked retinitis pigmentosa, a condition that causes vision loss due to RPGR gene mutations. The study tests the safety and effectiveness of a virus-based treatment (rAAV2tYF-GRK1-RPGR, a gene therapy) that might improve or stabilize vision. Participants are divided into groups to receive different doses of the treatment. Men with a confirmed RPGR mutation and vision issues from retinitis pigmentosa may be suitable for this study. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that you stop using anti-coagulant agents (medications that prevent blood clotting) within 7 days before the study treatment and systemic corticosteroids or other immunosuppressive medications within 3 months before joining the study.

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

Research has shown that rAAV2tYF-GRK1-RPGR, a gene therapy for X-linked retinitis pigmentosa, has undergone safety testing. In previous studies, participants generally tolerated this treatment well. Researchers tested different doses to determine the safest and most effective amount. Some side effects occurred, mostly mild, such as eye irritation or temporary changes in vision. This therapy uses a virus to deliver new genes, designed to be safe and not cause illness. As this is an early-phase trial, safety remains a primary focus, and ongoing studies aim to ensure safety for all participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about rAAV2tYF-GRK1-RPGR for retinitis pigmentosa because it offers a novel approach through gene therapy. Unlike existing treatments that focus on slowing vision loss, this gene therapy aims to address the root cause by delivering a correct copy of the RPGR gene directly to the retinal cells. This innovative method has the potential to halt or even reverse vision deterioration, which could significantly improve quality of life for patients. Additionally, the use of an adeno-associated viral vector (AAV) for gene delivery is designed to be safe and efficient, potentially making it a breakthrough in treating genetic eye diseases.

What evidence suggests that this gene therapy might be an effective treatment for retinitis pigmentosa?

Studies have shown that the gene therapy treatment, rAAV2tYF-GRK1-RPGR, holds promise for patients with X-linked retinitis pigmentosa, a genetic eye condition. In earlier research, 69% of patients with a visible ellipsoid zone, a part of the retina, experienced improvement just a few months after treatment. This suggests that the therapy can help restore some vision. In this trial, participants will receive different doses of the rAAV2tYF-GRK1-RPGR study drug to evaluate its safety and effectiveness. The treatment uses a virus to deliver a healthy gene, which helps correct the faulty gene causing the disease. Overall, early findings indicate this gene therapy could be a hopeful option for improving vision in affected individuals. ^{1 2 3 6 7}

Who Is on the Research Team?

Matthew Feinsod, MD

Principal Investigator

Applied Genetics Technologies Corporation

Are You a Good Fit for This Trial?

This trial is for males aged 6-50 with X-linked retinitis pigmentosa (XLRP) due to RPGR gene mutations. Participants must have a certain level of visual acuity, not better than 20/32 and no worse than 20/200. They should not have other retinal diseases or previous AAV gene therapy treatments.

Inclusion Criteria

I am a male with a confirmed RPGR mutation.

I have been diagnosed with X-linked retinitis pigmentosa.

Ability to perform tests of visual and retinal function and structure and ability to comply with other research procedures

Exclusion Criteria

I do not have eye conditions like glaucoma or diabetic retinopathy that could complicate surgery.

I have never received AAV gene therapy before.

I haven't taken blood thinners in the last 7 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single subretinal injection of the study agent in one eye

36 months

15 visits over 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Annual visits at years 4 and 5

Long-term follow-up

Long-term safety evaluations conducted annually

Years 4 and 5

What Are the Treatments Tested in This Trial?

Interventions

• rAAV2tYF-GRK1-RPGR

Trial Overview The study tests the safety and effectiveness of rAAV2tYF-GRK1-RPGR, a genetic treatment delivered via a virus vector, in patients with XLRP caused by specific RPGR mutations.

How Is the Trial Designed?

Group I: Group 6 Phase 1/2 Dose Escalation Experimental Treatment 1 Intervention

Male subjects at least 18 y/o treated with Dose 6 of rAAV2tYF-GRK1-RPGR study drug.

Group II: Group 5 Phase 1/2 Dose Escalation Experimental Treatment 1 Intervention

Male subjects at least 18 y/o treated with Dose 5 of rAAV2tYF-GRK1-RPGR study drug.

Group III: Group 4 Phase 1/2 Dose Escalation Experimental Treatment 1 Intervention

Group 4 male subjects at least 6 y/o treated with Dose 3 of rAAV2tYF-GRK1-RPGR study drug.

Group IV: Group 3 Phase 1/2 Dose Escalation Experimental Treatment 1 Intervention

Group 3 male subjects at least 18 y/o treated with Dose 3 of rAAV2tYF-GRK1-RPGR study drug.

Group V: Group 2: Phase 1/2 Dose Escalation Experimental Treatment 1 Intervention

Male subjects at least 18 y/o treated with Dose 2 of rAAV2tYF-GRK1-RPGR study drug.

Group VI: Group 1: Phase 1/2 Dose Escalation Experimental Treatment 1 Intervention

Male subjects at least 18 y/o treated with Dose 1 of rAAV2tYF-GRK1-RPGR study drug.

Who Is Running the Clinical Trial?

Beacon Therapeutics

Lead Sponsor

Trials

13

Recruited

390+

Applied Genetic Technologies Corp

Lead Sponsor

Trials

11

Recruited

350+

Applied Genetic Technologies Corp

Lead Sponsor

Trials

11

Recruited

350+

Published Research Related to This Trial

In a study involving a canine model of X-linked retinitis pigmentosa (XLRP), the rAAV2tYF-GRK1-hRPGRco gene therapy showed promising results in correcting early disease markers without significant ocular complications, except for some retinal detachment in the highest dose group.

The therapy demonstrated a dose-dependent expression of the RPGR gene and a rescue effect on retinal structure, supporting its potential for clinical trials in humans with RPGR mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy. Song, C., Dufour, VL., Cideciyan, AV., et al.[2021]

The rAAV vector AGTC-501, designed to deliver the RPGR gene, was well tolerated in a safety study involving 60 Rd9 mice, with no systemic toxicity or significant ocular changes observed after subretinal injection.

The study demonstrated dose-dependent expression of the RPGR protein in treated mice, supporting the potential efficacy of AGTC-501 for treating retinitis pigmentosa caused by RPGR mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicology and Pharmacology of an AAV Vector Expressing Codon-Optimized RPGR in RPGR-Deficient Rd9 Mice. Song, C., Conlon, TJ., Deng, WT., et al.[2020]

In a study of 18 male patients with RPGR X-linked retinitis pigmentosa, significant thinning of the foveal photoreceptor outer segments was observed compared to 30 normal subjects, indicating a potential reason for their reduced visual acuity.

The mean outer segment thickness in RPGR patients was approximately 35.5 µm, while normal subjects had a thickness of about 61.9 µm, highlighting the need to consider these measurements when evaluating the effectiveness of retinal gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa. Menghini, M., Jolly, JK., Nanda, A., et al.[2023]

In a mouse model of retinitis pigmentosa (RP), gene therapy was able to halt degeneration and restore function when administered at early, mid, or late stages of the disease, showing that treatment can be effective even after disease onset.

The study highlights a broad therapeutic time window for gene therapy in RP, suggesting that patients diagnosed after significant photoreceptor loss can still benefit from treatment, emphasizing the need to improve transduction efficiency for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Halting progressive neurodegeneration in advanced retinitis pigmentosa. Koch, SF., Tsai, YT., Duong, JK., et al.[2018]

The first-in-human phase 1/2 clinical trial of retinal gene therapy for X-linked retinitis pigmentosa (RP) involving 18 patients showed that the treatment was generally safe, with only mild steroid-responsive inflammation noted at higher doses.

Significant visual field improvements were observed in six patients starting from one month after treatment and lasting through the 6-month follow-up, indicating potential efficacy of the gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Cehajic-Kapetanovic, J., Xue, K., Martinez-Fernandez de la Camara, C., et al.[2023]

Gene augmentation therapy using adeno-associated virus vectors has shown effectiveness in treating canine models of X-linked retinitis pigmentosa, with preserved photoreceptor structure and function observed after treatment.

The therapy resulted in significant improvements in both rod and cone photoreceptor function, suggesting a promising pathway for future human clinical applications in treating hereditary retinal blindness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Beltran, WA., Cideciyan, AV., Lewin, AS., et al.[2022]

Citations

1. ajo.com ajo.com/article/S0002-9394(24)00552-X/fulltext

Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase ... To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa ( ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03316560

Safety and Efficacy of rAAV2tYF-GRK1-RPGR in Subjects ... This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector (rAAV2tYF-GRK1-RPGR) in patients with X-linked retinitis ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S000293942400552X

Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase ... To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7404825/

Dose Range Finding Studies with Two RPGR Transgenes ... These results support the selection and use of rAAV2tYF-GRK1-hRPGRco (AGTC-501) and guided the initial doses in clinical studies in patients with XLRP caused by ...

5. cgtlive.com cgtlive.com/view/agtc-501-efficacy-maintained-in-18-month-follow-up-data-for-x-linked-retinitis-pigmentosa

AGTC-501 Efficacy Maintained in 18-Month Follow Up ... Following injection of AGTC-501 for those with visible EZ at baseline, 69% experienced EZ recovery 3 to 6 months following treatment (9 of 13).

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39643074/

Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase ... To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa ( ...

7. scge.mcw.edu scge.mcw.edu/platform/data/clinicalTrials/report/NCT04850118

A Clinical Trial Evaluating the Safety and Efficacy ... This study will evaluate and compare the safety, efficacy, and tolerability of 2 doses of a recombinant adeno-associated virus vector (AGTC-501/laruparetigene ...