Gene Therapy for Retinitis Pigmentosa
Recruiting in Palo Alto (17 mi)
+1 other location
Age: Any Age
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Janssen Research & Development, LLC
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The purpose of this study is to assess the safety and tolerability of subretinal delivery of Adeno-associated Virus Vector (AAV5 hRKp.RPGR) gene therapy in adults and children with X-linked retinitis pigmentosa.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications.
What data supports the effectiveness of the treatment AAV5-hRKp.RPGR for retinitis pigmentosa?
Initial results from a clinical trial showed that the gene therapy improved visual fields in some patients with X-linked retinitis pigmentosa, and studies in dogs demonstrated preserved photoreceptor function and structure after treatment, suggesting potential effectiveness for humans.
12345Is gene therapy for Retinitis Pigmentosa generally safe in humans?
In early human trials, the gene therapy for Retinitis Pigmentosa showed no major safety concerns, although some patients experienced inflammation in the eye that responded to steroids. Animal studies also indicated that the treatment was well tolerated with no significant side effects.
12346How is the gene therapy treatment AAV5-hRKp.RPGR different from other treatments for retinitis pigmentosa?
The gene therapy treatment AAV5-hRKp.RPGR is unique because it uses a viral vector to deliver a healthy copy of the RPGR gene directly to the photoreceptor cells in the retina, aiming to correct the genetic defect causing retinitis pigmentosa. This approach is novel as it targets the root cause of the disease at the genetic level, unlike other treatments that may only address symptoms.
12346Eligibility Criteria
This trial is for adults and children who have already been treated with AAV5-hRKp.RPGR gene therapy in a previous study (MGT009) and are either currently enrolled or have completed another study (MGT010). Participants must understand the study's purpose, procedures, and agree to follow the protocol.Inclusion Criteria
Have been treated with AAV5-hRKp.RPGR in study MGT009 and have completed or is currently enrolled in Study MGT010
Must sign an informed consent form indicating that they understand the purpose and procedures of the study and are willing to participate
Willing to adhere to the protocol and long-term follow-up
Exclusion Criteria
There are no specific exclusion criteria to enroll in this study
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive subretinal delivery of AAV5 hRKp.RPGR gene therapy in the second eye
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
5.5 years
Yearly visits
Long-term monitoring
Participants are assessed yearly for changes in retinal sensitivity and visual acuity
5 years
Participant Groups
The trial is testing the safety of delivering a gene therapy called AAV5-hRKp.RPGR directly under the retina. It follows patients previously treated for X-linked retinitis pigmentosa to see how they do over time without additional intervention.
3Treatment groups
Experimental Treatment
Group I: Cohort 3Experimental Treatment1 Intervention
The participants who are not willing to undergo surgery or are not eligible for surgery will be assessed in this cohort. They will be assessed yearly until 5 years after their initial eye surgery in previous study MGT009.
Group II: Cohort 2Experimental Treatment1 Intervention
Participants will receive the treatment dose of AAV5 hRKp.RPGR under the retina (low-dose or intermediate-dose) on Day 1 in the second eye once the safety will be determined in Cohort 1.
Group III: Cohort 1Experimental Treatment1 Intervention
Participants will receive a dose of AAV5 hRKp.RPGR under the retina (low-dose or intermediate-dose) on Day 1 depending on the dosage administered in study MGT009 (NCT03252847) in the past. After receiving the treatment, participants will be assessed for safety.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Michigan Kellogg Eye CenterAnn Arbor, MI
Massachusetts Eye and Ear InfirmaryBoston, MA
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Who Is Running the Clinical Trial?
Janssen Research & Development, LLCLead Sponsor
References
Toxicology and Pharmacology of an AAV Vector Expressing Codon-Optimized RPGR in RPGR-Deficient Rd9 Mice. [2020]Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated AAV2tYF-GRK1-RPGRco, to treat retinitis pigmentosa (RP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The vector contains a codon-optimized human RPGR cDNA (RPGRco) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1, GRK1) and is packaged in an AAV2 capsid with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a safety and potency study of this vector administered by subretinal a injection in the naturally occurring RPGR-deficient Rd9 mouse model. Sixty Rd9 mice (20 per group) received a subretinal injection in the right eye of vehicle (control) or AAV2tYF-GRK1-RPGRco at one of two dose levels (4 × 108 or 4 × 109 vg/eye) and were followed for 12 weeks after injection. Vector injections were well tolerated, with no systemic toxicity. There was a trend towards reduced electroretinography b-wave amplitudes in the high vector dose group that was not statistically significant. There were no clinically important changes in hematology or clinical chemistry parameters and no vector-related ocular changes in life or by histological examination. Dose-dependent RPGR protein expression, mainly in the inner segment of photoreceptors and the adjacent connecting cilium region, was observed in all vector-treated eyes examined. Sequence integrity of the codon-optimized RPGR was confirmed by sequencing of PCR-amplified DNA, or cDNA reverse transcribed from total RNA extracted from vector-treated retinal tissues, and by sequencing of RPGR protein obtained from transfected HEK 293 cells. These results support the use of rAAV2tYF-GRK1-RPGRco in clinical studies in patients with XLRP caused by RPGR mutations.
Molecular Strategies for RPGR Gene Therapy. [2023]Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%-20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, characteristic for its early onset and rapid progression to blindness in young people. At present there is no cure for RPGR-related retinal disease. Recently, however, there have been important advances in RPGR research from bench to bedside that increased our understanding of RPGR function and led to the development of potential therapies, including the progress of adeno-associated viral (AAV)-mediated gene replacement therapy into clinical trials. This manuscript discusses the advances in molecular research, which have connected the RPGR protein with an important post-translational modification, known as glutamylation, that is essential for its optimal function as a key regulator of photoreceptor ciliary transport. In addition, we review key pre-clinical research that addressed challenges encountered during development of therapeutic vectors caused by high infidelity of the RPGR genomic sequence. Finally, we discuss the structure of three current phase I/II clinical trials based on three AAV vectors and RPGR sequences and link the rationale behind the use of the different vectors back to the bench research that led to their development.
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.
RPGR gene therapy presents challenges in cloning the coding sequence. [2023]Introduction: Currently, there are three Phase I/II clinical trials based on gene therapy ongoing to test different AAV.RPGR or deleted RPGR vectors on patients affected by X-linked retinitis pigmentosa. These three vectors differ in the adeno-associated viral (AAV) vector capsid used, and the coding sequences: two contain codon optimized versions of RPGR which give the full-length protein, whilst the third uses a wild-type sequence that contains a large deletion encoding part of the functional domain of the RPGR protein.Areas covered: This review approaches the different studies that have led to the initiation of three different clinical trials for RPGR related X-linked retinitis pigmentosa.Expert opinion: The development of a gene therapy vector to deliver a normal copy of the RPGR gene into the photoreceptors has presented a challenge for the scientific community. The instability of its sequence and the fact that its function is not well understood can lead to the production of a nonfunctional or deleterious protein for the human retina. Since the RPGR protein undergoes post-translational glutamylation in the protein domain that may be particularly affected by gene instability, a functional assay of glutamylation is essential to verify the correct coding sequence.
Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. [2022]Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.
Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy. [2021]Recombinant adeno-associated viral (rAAV) vector-mediated gene therapy is being developed to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. In preparation for a clinical gene therapy trial, we conducted dose range finding (DRF) studies with an AAV2 capsid with three surface tyrosine residues changed to phenylalanine (AAV2tYF) vector administered by subretinal injection in a naturally occurring RPGR-mutant canine model (XLPRA2) to compare two different human RPGR (hRPGR) transgenes and to establish a reasonable starting dose for a clinical trial. Different dose levels of two candidate vectors (0.15 mL at 1.2 × 1010-3.0 × 1012 vg/mL of rAAV2tYF-GRK1-hRPGRco or 4 × 1010-3.0 × 1012 vg/mL of rAAV2tYF-GRK1-hRPGRstb), 6.0 × 1011 vg/mL rAAV5-GRK1-hRPGRco reference vector or Vehicle were subretinally administered, and the dogs were followed for 8 weeks postdose. Ophthalmic examinations, analyses of retinal structure by in vivo imaging using confocal scanning laser ophthalmoscopy (cSLO)/optical coherence tomography (OCT) in the Lower (4.0 × 1010 vg/mL) and Lowest (1.2 × 1010 vg/mL) Doses, immunological responses by cell based assays or enzyme-linked immunosorbent assay, RPGR transgene expression, and reversal of opsin mislocalization by immunohistochemistry were performed. No sustained signs of ocular discomfort or ophthalmic complications were noted in any of the injected eyes except some in the High Dose group (3.0 × 1012 vg/mL), which showed signs of retinal detachment and inflammation. A change in fundus reflectivity suggestive of a rescue effect was seen in the High, Mid (6.0 × 1011 vg/mL), and Low (1.2 × 1011 vg/mL) Dose groups. cSLO/OCT demonstrated qualitative and quantitative evidence of rescue effect in eyes treated with the Lower Dose. Anti-hRPGR antibodies were absent, but neutralizing antibody titers against AAV2 were detected in all animals dosed with rAAV2tYF in an apparent dose-related pattern. RPGR expression was stronger for rAAV2tYF-GRK1-hRPGRco compared to rAAV2tYF-GRK1-hRPGRstb at all dose levels. Subretinal administration of rAAV2tYF-GRK1-hRPGRco and rAAV2tYF-GRK1-hRPGRstb both corrected rod and cone opsin mislocalization, two early markers of disease in the XLPRA2 canine model of RPGR-XLRP. 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 RPGR mutations.