Gene Therapy for Retinitis Pigmentosa

(HORIZON Trial)

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

29 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment rAAV2tYF-GRK1-RPGR for retinitis pigmentosa?

Research in animal models, like dogs, shows that gene therapy targeting the RPGR gene can preserve vision by maintaining the structure and function of eye cells. In early human trials, some patients experienced improvements in their visual field, suggesting potential benefits of this treatment. ^{1 2 3 4 5}

Is the gene therapy rAAV2tYF-GRK1-RPGR safe for humans?

In early human trials, the gene therapy rAAV2tYF-GRK1-RPGR was generally safe, with some patients experiencing mild inflammation that responded to steroids. Animal studies also showed no major safety concerns, supporting its use in humans. ^{4 5 6 7 8}

How does the treatment rAAV2tYF-GRK1-RPGR differ from other treatments for retinitis pigmentosa?

The treatment rAAV2tYF-GRK1-RPGR is unique because it uses gene therapy to target the specific genetic mutation causing retinitis pigmentosa, delivering a corrected version of the RPGR gene directly to the retina using a modified virus. This approach aims to restore function in the affected photoreceptor cells, which is different from other treatments that may only manage symptoms rather than address the underlying genetic cause. ^{4 5 6 7 8}

What is the purpose of this trial?

This trial is testing a new treatment for people with a genetic eye disease that causes vision loss. The treatment uses a harmless virus to deliver a healthy gene directly into the eye. This could help improve or stabilize their vision. The study will monitor safety and effectiveness over time. This marks a significant advance in treating genetic eye diseases.

Research Team

Matthew Feinsod, MD

Principal Investigator

Applied Genetics Technologies Corporation

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

References

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

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa. [2023]

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

Halting progressive neurodegeneration in advanced retinitis pigmentosa. [2018]

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

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. [2022]

5. United States 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. [2023]

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

Toxicology and Pharmacology of an AAV Vector Expressing Codon-Optimized RPGR in RPGR-Deficient Rd9 Mice. [2020]

7. United States 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. [2021]

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

Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations. [2022]