Gene Therapy with Light-Stimulating Glasses for Retinitis Pigmentosa

(PIONEER Trial)

Recruiting at 2 trial locations

Overseen By Magali Taiel, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: GenSight Biologics

Disqualifiers: Gene therapy, Ocular surgery, Retinal detachment, 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: 52 weeks

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It might be best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment GS030 for Retinitis Pigmentosa?

Research shows that optogenetic therapy, which involves using gene delivery to make certain retinal cells light-sensitive, has restored vision in animal models of Retinitis Pigmentosa. Additionally, similar gene therapies have shown promise in early human trials, improving visual fields in some patients. ^{1 2 3 4 5}

Is the gene therapy with light-stimulating glasses for retinitis pigmentosa safe for humans?

The gene therapy, including versions like GS030, has been tested in humans, and the main safety concern was mild inflammation in some patients, which responded to treatment. Overall, no major safety issues were reported in these trials. ^{1 2 4 6 7}

What makes the treatment GS030-DP unique for retinitis pigmentosa?

The treatment GS030-DP is unique because it combines gene therapy with light-stimulating glasses to restore vision in retinitis pigmentosa patients by making surviving retinal cells sensitive to light, a novel approach compared to traditional treatments that do not address the underlying genetic causes of the disease. ^{1 3 8 9 10}

What is the purpose of this trial?

This trial is testing a new gene therapy injected into the eye and special light-stimulating glasses for patients with a specific type of vision loss called non-syndromic Retinitis Pigmentosa. The gene therapy aims to fix genetic problems in the eye, while the glasses help activate the treated cells. Gene therapy has shown promise in treating retinal diseases.

Eligibility Criteria

Adults aged 18-75 with non-syndromic Retinitis Pigmentosa (RP), confirmed by specific tests, who have not had gene therapy before or significant eye surgery within the last 3 months. Participants should have a certain range of visual acuity and refractive error, as well as an appropriate interpupillary distance.

Inclusion Criteria

Visual acuity in the dose-escalation cohorts of no better LP

Relatively preserved ganglion cell layer volume and retinal nerve fiber layer thickness as measured with SD-OCT

Interpupillary distance of ≥51 mm and ≤72 mm

Exclusion Criteria

I have never received gene therapy.

I have not had major eye surgery in the last 3 months.

I have a condition affecting my eye's central vision due to vitreo-macular adhesion or similar issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravitreal injection of GS030-DP and repeated light stimulation using GS030-MD

52 weeks

Multiple visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Extension cohort at the highest well-tolerated dose with additional subjects

Varies

Treatment Details

Interventions

• GS030-DP
• GS030-MD

Trial Overview The trial is testing GS030-DP, a new gene therapy given through an injection in the eye, alongside GS030-MD, special glasses that provide light stimulation. The study aims to find out how safe these treatments are and what doses are tolerable for people with RP.

Participant Groups

Group I: Cohort Experimental Treatment 1 Intervention

3 dose escalation cohorts (low, medium and high dose) with 3 subjects per cohort followed by an extension cohort at the highest-well tolerated dose with 3 to 9 subjects.

GS030-DP is already approved in European Union, United States for the following indications:

Approved in European Union as GS030 for:

• Orphan Drug Designation for Retinitis Pigmentosa

Approved in United States as GS030 for:

• Orphan Drug Designation for Retinitis Pigmentosa
• Fast Track Status for Retinitis Pigmentosa

Who Is Running the Clinical Trial?

GenSight Biologics

Lead Sponsor

Trials

9

Recruited

320+

Findings from Research

Optogenetic tools, which involve gene delivery of light-activated channels to surviving retinal cells, have shown promise in restoring photosensitivity in animal models of retinitis pigmentosa, a condition affecting two million people globally.

Recent in vitro studies using post-mortem human retinas suggest that this optogenetic approach has significant translational potential for treating RP, although there are still limitations to consider in its application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optogenetic therapy for retinitis pigmentosa. Busskamp, V., Picaud, S., Sahel, JA., et al.[2012]

There are over 100 drugs currently in development for Retinitis Pigmentosa (RP), with 50% being advanced therapy medicinal products (ATMPs), highlighting a significant push towards innovative treatments for this condition.

Gene therapies aim to restore vision by targeting non-functional photoreceptors, while cell therapies offer broader applications as they do not depend on the presence of viable photoreceptors, making them potentially more accessible for patients at various disease stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Future Treatment of Retinitis Pigmentosa. Cross, N., van Steen, C., Zegaoui, Y., et al.[2022]

The study demonstrates that bReaChES, a high sensitivity opsin, can restore vision in a mouse model of severe retinal degeneration by making normally light-insensitive retinal neurons responsive to light, achieving action potentials at levels comparable to bright indoor lighting.

Intravitreal gene therapy using bReaChES not only restored visual responses in treated mice but also showed potential for application in humans, as human retinal explants successfully transduced with the treatment vector, indicating its feasibility for future clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optogenetic restoration of high sensitivity vision with bReaChES, a red-shifted channelrhodopsin. Too, LK., Shen, W., Protti, DA., et al.[2023]

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 study developed a combination gene therapy using dual adeno-associated viruses (AAVs) that both ablate the mutated Rho gene and replace it with a healthy version, showing significant improvements in photoreceptor structure and function in mouse models of retinitis pigmentosa (RP).

Results indicated that the ablate-and-replace therapy led to a 17% to 36% increase in outer nuclear layer thickness and significantly better preservation of electroretinographic responses compared to gene replacement therapy alone, suggesting its potential as a universal treatment for various Rho mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clustered Regularly Interspaced Short Palindromic Repeats-Based Genome Surgery for the Treatment of Autosomal Dominant Retinitis Pigmentosa. Tsai, YT., Wu, WH., Lee, TT., et al.[2022]

Over the past 20 years, various proof-of-concept gene therapy studies have been conducted for autosomal dominant retinitis pigmentosa caused by mutations in the rhodopsin gene, showcasing different approaches and strategies.

The review compiles significant results from these studies, highlighting advancements in gene silencing and delivery methods that could lead to potential treatments for this form of retinal degeneration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress in Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa. Sudharsan, R., Beltran, WA.[2020]

The study developed Span-polyarginine (SP-PA) nanoparticles for delivering the PRPF31 gene to treat autosomal dominant retinitis pigmentosa (adRP), showing effective gene transfer in a mouse model with a specific mutation.

Treatment with SP-PA nanoparticles resulted in significant improvements in visual acuity and retinal thickness in the affected mice, indicating potential efficacy for this gene therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa. Pensado, A., Diaz-Corrales, FJ., De la Cerda, B., et al.[2018]

This study successfully demonstrated the expression of human rhodopsin in bipolar cells of a mouse model of retinal degeneration (rd1) using modified AAV capsids, which could enhance optogenetic therapy for vision restoration.

The research also introduced the first instance of human cone opsin expression in bipolar cells, expanding the optogenetic toolkit and paving the way for potential future trials aimed at restoring vision in human patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV Induced Expression of Human Rod and Cone Opsin in Bipolar Cells of a Mouse Model of Retinal Degeneration. McClements, ME., Staurenghi, F., Visel, M., et al.[2022]

The study demonstrated successful vision restoration in animal models of retinal degeneration using a new opsin called MCO1, delivered via a safe viral method, which significantly improved visually guided behavior.

MCO1 showed effectiveness at much lower light intensities compared to traditional opsins, suggesting it could be a promising gene therapy for various retinal diseases without compromising retinal cell viability under chronic light exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoring vision in mice with retinal degeneration using multicharacteristic opsin. Wright, W., Gajjeraman, S., Batabyal, S., et al.[2020]

The study demonstrated successful vision restoration in animal models of retinal degeneration using a new opsin called MCO1, delivered via a safe viral method, which significantly improved visually guided behavior.

MCO1 showed effectiveness at much lower light intensities compared to traditional opsins, suggesting it could be a promising gene therapy for various retinal diseases without compromising retinal cell viability under chronic light exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoring vision in mice with retinal degeneration using multicharacteristic opsin. Wright, W., Gajjeraman, S., Batabyal, S., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Optogenetic therapy for retinitis pigmentosa. [2012]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Current and Future Treatment of Retinitis Pigmentosa. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Optogenetic restoration of high sensitivity vision with bReaChES, a red-shifted channelrhodopsin. [2023]

4. 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]

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

Clustered Regularly Interspaced Short Palindromic Repeats-Based Genome Surgery for the Treatment of Autosomal Dominant Retinitis Pigmentosa. [2022]

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

Progress in Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa. [2020]

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

Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa. [2018]

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

AAV Induced Expression of Human Rod and Cone Opsin in Bipolar Cells of a Mouse Model of Retinal Degeneration. [2022]

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

Restoring vision in mice with retinal degeneration using multicharacteristic opsin. [2020]

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

Restoring vision in mice with retinal degeneration using multicharacteristic opsin. [2022]