Gene Therapy with Light-Stimulating Glasses for Retinitis Pigmentosa
(PIONEER Trial)
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: GenSight Biologics
Disqualifiers: Gene therapy, Ocular surgery, Retinal detachment, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
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.
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.
12345Is 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.
12467What 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.
138910Eligibility 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
+5 more
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.
+8 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: CohortExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UPMC Eye CenterPittsburgh, PA
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Who Is Running the Clinical Trial?
GenSight BiologicsLead Sponsor
References
Optogenetic therapy for retinitis pigmentosa. [2012]Retinitis pigmentosa (RP) refers to a diverse group of progressive, hereditary diseases of the retina that lead to incurable blindness and affect two million people worldwide. Artificial photoreceptors constructed by gene delivery of light-activated channels or pumps ('optogenetic tools') to surviving cell types in the remaining retinal circuit has been shown to restore photosensitivity in animal models of RP at the level of the retina and cortex as well as behaviorally. The translational potential of this optogenetic approach has been evaluated using in vitro studies involving post-mortem human retinas. Here, we review recent developments in this expanding field and discuss the potential and limitations of optogenetic engineering for the treatment of RP.
Current and Future Treatment of Retinitis Pigmentosa. [2022]Retinitis Pigmentosa (RP) is a group of inherited retinal dystrophies (IRDs) characterised by progressive vision loss. Patients with RP experience a significant impact on daily activities, social interactions, and employment, reducing their quality of life. Frequent delays in referrals and no standard treatment for most patients also contribute to the high unmet need for RP. This paper aims to describe the evolving therapeutic landscape for RP including the rationale for advanced therapy medicinal products (ATMPs). A review of available data was conducted in three stages: (1) a search of publicly available literature; (2) qualitative research with physicians treating RP patients in France, Germany, Italy, Spain, and the UK; and (3) a review of leading candidates in the RP pipeline. Globally, there are currently over 100 drugs in development for RP; 50% of which are ATMPs. Amongst the 15 cell and gene therapies in late-stage development, 5 leading candidates have been selected to profile based on the development stage, drug target and geography: gene therapies AGN-151597, GS-030 and VMCO-1 and human stem cell therapies jCell and ReN-003. Hereditary retinal diseases are suitable for treatment with cell and gene therapies due to the accessibility of the retina and its immune privilege and compartmentalisation. Therapeutic approaches that aim to rescue photoreceptors (eg gene therapies) require that non-functional target cells are still present, whereas other therapies (eg cell therapies) are not reliant on the presence of viable photoreceptors. Gene therapies may be attractive as their fundamental goal is to restore vision; however, cell therapies will likely have a broader application and do not rely on genetic testing, which can delay treatment. Ensuring effective therapeutic options for RP patients across disease stages requires the continued diversification and advancement of the development pipeline, and sustained efforts to promote early patient identification and timely diagnosis.
Optogenetic restoration of high sensitivity vision with bReaChES, a red-shifted channelrhodopsin. [2023]The common final pathway to blindness in many forms of retinal degeneration is the death of the light-sensitive primary retinal neurons. However, the normally light-insensitive second- and third-order neurons persist optogenetic gene therapy aims to restore sight by rendering such neurons light-sensitive. Here, we investigate whether bReaChES, a newly described high sensitivity Type I opsin with peak sensitivity to long-wavelength visible light, can restore vision in a murine model of severe early-onset retinal degeneration. Intravitreal injection of an adeno-associated viral vector carrying the sequence for bReaChES downstream of the calcium calmodulin kinase IIα promoter resulted in sustained retinal expression of bReaChES. Retinal ganglion cells (RGCs) expressing bReaChES generated action potentials at light levels consistent with bright indoor lighting (from 13.6 log photons cm-2 s-1). They could also detect flicker at up to 50 Hz, which approaches the upper temporal limit of human photopic vision. Topological response maps of bReaChES-expressing RGCs suggest that optogenetically activated RGCs may demonstrate similar topographical responses to RGCs stimulated by photoreceptor activation. Furthermore, treated dystrophic mice displayed restored cortical neuronal activity in response to light and rescued behavioral responses to a looming stimulus that simulated an aerial predator. Finally, human surgical retinal explants exposed to the bReaChES treatment vector demonstrated transduction. Together, these findings suggest that intravitreal gene therapy to deliver bReaChES to the retina may restore vision in human retinal degeneration in vivo at ecologically relevant light levels with spectral and temporal response characteristics approaching those of normal human photopic vision.
Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. [2023]Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.
Clustered Regularly Interspaced Short Palindromic Repeats-Based Genome Surgery for the Treatment of Autosomal Dominant Retinitis Pigmentosa. [2022]To develop a universal gene therapy to overcome the genetic heterogeneity in retinitis pigmentosa (RP) resulting from mutations in rhodopsin (RHO).
Progress in Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa. [2020]This brief review summarizes the major proof-of-concept gene therapy studies for autosomal dominant retinitis pigmentosa (RP) caused by mutations in the rhodopsin gene (RHO-adRP) that have been conducted over the past 20 years in various animal models. We have listed in tabular form the various approaches, gene silencing reagents, gene delivery strategies, and salient results from these studies.
Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa. [2018]Retinitis pigmentosa (RP) is the most common cause of inherited blindness in adults. Mutations in the PRPF31 gene produce autosomal dominant RP (adRP). To date there are no effective treatments for this disease. The purpose of this study was to design an efficient non-viral vector for human PRPF31 gene delivery as an approach to treat this form of adRP. Span based nanoparticles were developed to mediate gene transfer in the subretinal space of a mouse model of adRP carrying a point mutation (A216P) in the Prpf31 gene. Funduscopic examination, electroretinogram, optomotor test and optical coherence tomography were conducted to further in vivo evaluate the safety and efficacy of the nanosystems developed. Span-polyarginine (SP-PA) nanoparticles were able to efficiently transfect the GFP and PRPF31 plasmid in mice retinas. Statistically significant improvement in visual acuity and retinal thickness were found in Prpf31A216P/+ mice treated with the SP-PA-PRPF31 nanomedicine.
AAV Induced Expression of Human Rod and Cone Opsin in Bipolar Cells of a Mouse Model of Retinal Degeneration. [2022]Vision loss caused by inherited retinal degeneration affects millions of people worldwide, and clinical trials involving gene supplementation strategies are ongoing for select forms of the disease. When early therapeutic intervention is not possible and patients suffer complete loss of their photoreceptor cells, there is an opportunity for vision restoration techniques, including optogenetic therapy. This therapy provides expression of light-sensitive molecules to surviving cell types of the retina, enabling light perception through residual neuronal pathways. To this end, the bipolar cells make an obvious optogenetic target to enable upstream processing of visual signal in the retina. However, while AAV transduction of the bipolar cells has been described, the expression of human opsins in these cell types within a model of retinal degeneration (rd1) has been less successful. In this study, we have expanded the optogenetic toolkit and shown successful expression of human rhodopsin driven by an ON-bipolar cell promoter (Grm6) in the rd1 mouse model using modified AAV capsids (AAV2.4YF, AAV8.BP2, and AAV2.7m8) delivered via intraocular injection. We also show the first presentation of ectopic expression of human cone opsin in the bipolar cells of rd1 mice. These data provide evidence of an expansion of the optogenetic toolkit with the potential to restore useful visual function, setting the stage for future trials in human patients.
Restoring vision in mice with retinal degeneration using multicharacteristic opsin. [2020]Retinal degenerative diseases, such as retinitis pigmentosa (RP) and dry age-related macular degeneration, have led to loss of vision in millions of individuals. Currently, no surgical or medical treatment is available, although optogenetic therapies are in clinical development. We demonstrate vision restoration using multicharacteristics opsin (MCO1) in animal models with degenerated retina. MCO1 is reliably delivered to specific retinal cells via intravitreal injection of adeno-associated virus (vMCO1), leading to significant improvement in visually guided behavior conducted using a radial arm water maze. The time to reach the platform and the number of error arms decreased significantly after delivery of MCO1. Notably, the improvement in visually guided behavior was observed even at light intensity levels orders of magnitude lower than that required for channelrhodopsin-2 opsin. Viability of vMCO1-treated retina is not compromised by chronic light exposure. Safe virus-mediated MCO1 delivery has potential for effective gene therapy of diverse retinal degenerations in patients.
Restoring vision in mice with retinal degeneration using multicharacteristic opsin. [2022]Retinal degenerative diseases, such as retinitis pigmentosa (RP) and dry age-related macular degeneration, have led to loss of vision in millions of individuals. Currently, no surgical or medical treatment is available, although optogenetic therapies are in clinical development. We demonstrate vision restoration using multicharacteristics opsin (MCO1) in animal models with degenerated retina. MCO1 is reliably delivered to specific retinal cells via intravitreal injection of adeno-associated virus (vMCO1), leading to significant improvement in visually guided behavior conducted using a radial arm water maze. The time to reach the platform and the number of error arms decreased significantly after delivery of MCO1. Notably, the improvement in visually guided behavior was observed even at light intensity levels orders of magnitude lower than that required for channelrhodopsin-2 opsin. Viability of vMCO1-treated retina is not compromised by chronic light exposure. Safe virus-mediated MCO1 delivery has potential for effective gene therapy of diverse retinal degenerations in patients.