Gene Therapy with SPVN06 for Cone-Rod Dystrophy
(PRODYGY Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: SparingVision
Must not be taking: Immunosuppressants, Corticosteroids, others
Disqualifiers: Gene therapy, Cancer, Glaucoma, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new treatment for patients with advanced vision problems caused by specific genetic mutations. The study aims to determine the appropriate dose and evaluate its effectiveness.
Will I have to stop taking my current medications?
The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressive therapies or treatments that affect the immune system, you may need to stop them as they are listed in the exclusion criteria.
What data supports the effectiveness of the treatment SPVN06 for Cone-Rod Dystrophy?
Gene therapy has shown promise in treating similar eye conditions, like retinitis pigmentosa and cone-rod dystrophy, by improving vision and preserving photoreceptor cells in animal models and early human trials. This suggests that SPVN06, as a gene therapy, might also help in treating Cone-Rod Dystrophy by potentially restoring some vision and delaying further vision loss.
12345What safety data exists for SPVN06 gene therapy in humans?
There is no specific safety data available for SPVN06 gene therapy in humans from the provided research articles.
678910What makes the SPVN06 treatment unique for cone-rod dystrophy?
SPVN06 is a gene therapy specifically designed for cone-rod dystrophy, which is a novel approach as there are no standard treatments for this condition. Unlike other treatments that may require multiple doses or different administration routes, SPVN06 is likely administered as a one-time treatment, potentially offering a long-term solution.
1291112Eligibility Criteria
Adults over 18 with advanced Retinal Cone Dystrophy (RCD) due to specific genetic mutations, who can consent and follow study rules. They must use birth control if they can have children, be in good general health without serious heart, liver or kidney issues, and not pregnant or breastfeeding. Vision loss should be similar in both eyes.Inclusion Criteria
I am 18 years old or older.
I have been diagnosed with refractory celiac disease.
Documented preservation of cone inner and outer segments considered adequate by the investigator
+11 more
Exclusion Criteria
Participation in another clinical trial with investigational medicinal product within specified timeframe
I have not had COVID-19 in the last 2 weeks.
Known allergies to specified constituents or drugs
+37 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose-Escalation
Participants receive a single subretinal injection of SPVN06 at varying doses to assess safety and tolerability
1 day
1 visit (in-person)
Controlled Extension
Participants receive a single subretinal injection of SPVN06 at recommended doses in a controlled, double-masked, randomized setting
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety, tolerability, and preliminary efficacy, including viral shedding, immune response, and biomarker exploration
5 years
Participant Groups
The trial is testing SPVN06 gene therapy for RCD in two parts: first, different doses are given to find the safest one; second, patients are randomly put into three groups to compare results while neither doctors nor patients know who gets what treatment.
6Treatment groups
Experimental Treatment
Active Control
Group I: Step 2 : SPVN06 Dose Recommended 2Experimental Treatment1 Intervention
Participants will receive a single subretinal injection of SPVN06 recommended dose 2 on Day 0
Group II: Step 2 : SPVN06 Dose Recommended 1Experimental Treatment1 Intervention
Participants will receive a single subretinal injection of SPVN06 recommended dose 1 on Day 0
Group III: Step 1 : SPVN06 dose 3Experimental Treatment1 Intervention
Participants will receive a single subretinal injection of SPVN06 Dose 3 on Day 0
Group IV: Step 1 : SPVN06 dose 2Experimental Treatment1 Intervention
Participants will receive a single subretinal injection of SPVN06 Dose 2 on Day 0
Group V: Step 1 : SPVN06 dose 1Experimental Treatment1 Intervention
Participants will receive a single subretinal injection of SPVN06 Dose 1 on Day 0.
Group VI: Step 2 : Control groupActive Control1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Natalie AnthonyPittsburgh, PA
Bascom Palmer Eye Institute/University of MiamiMiami, FL
Casey Eye InstitutePortland, OR
UPMC Eye CenterPittsburgh, PA
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Who Is Running the Clinical Trial?
SparingVisionLead Sponsor
References
Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. [2012]Retinitis pigmentosa (RP) is a group of genetically heterogeneous, severe retinal diseases commonly leading to legal blindness. Mutations in the CNGB1a subunit of the rod cyclic nucleotide-gated (CNG) channel have been found to cause RP in patients. Here, we demonstrate the efficacy of gene therapy as a potential treatment for RP by means of recombinant adeno-associated viral (AAV) vectors in the CNGB1 knockout (CNGB1(-/-)) mouse model. To enable efficient packaging and rod-specific expression of the relatively large CNGB1a cDNA (~4 kb), we used an AAV expression cassette with a short rod-specific promoter and short regulatory elements. After injection of therapeutic AAVs into the subretinal space of 2-week-old CNGB1(-/-) mice, we assessed the restoration of the visual system by analyzing (i) CNG channel expression and localization, (ii) retinal function and morphology and (iii) vision-guided behavior. We found that the treatment not only led to expression of full-length CNGB1a, but also restored normal levels of the previously degraded CNGA1 subunit of the rod CNG channel. Both proteins co-localized in rod outer segments and formed regular CNG channel complexes within the treated area of the CNGB1(-/-) retina, leading to significant morphological preservation and a delay of retinal degeneration. In the electroretinographic analysis, we also observed restoration of rod-driven light responses. Finally, treated CNGB1(-/-) mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this work provides a proof-of-concept for the treatment of rod channelopathy-associated RP by AAV-mediated gene replacement.
Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. [2021]For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.
Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. [2022]Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness.
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.
Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa. [2021]Deficiencies in rod-specific cyclic guanosine monophosphate (cGMP) phosphodiesterase-6 (PDE6) are the third most common cause of autosomal recessive retinitis pigmentosa (RP). Previously, viral gene therapy approaches on pre-clinical models with mutations in PDE6 have demonstrated that the photoreceptor cell survival and visual function can be rescued when the gene therapy virus is delivered into the subretinal space before the onset of disease. However, no studies have currently been published that analyze rescue effects after disease onset, a time when human RP patients are diagnosed by a clinician and would receive the treatment. We utilized the AAV2/8(Y733F)-Rho-Pde6α gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6α(D670G). These mice were previously shown to have long-term photoreceptor cell rescue when this gene therapy virus was delivered before the onset of disease. Now, we have determined that subretinal transduction of this rod-specific transgene at post-natal day (P) 21, when approximately half of the photoreceptor cells have undergone degeneration, is more efficient in rescuing cone than rod photoreceptor function long term. Therefore, AAV2/8(Y733F)-Rho-Pde6α is an effective gene therapy treatment that can be utilized in the clinical setting, in human patients who have lost portions of their peripheral visual field and are in the mid-stage of disease when they first present to an eye-care professional.
Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. [2017]To provide an initial assessment of the safety of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in adults and children with retinal degeneration caused by RPE65 mutations.
Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. [2022]Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study.
Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence. [2020]Subretinal gene therapy trials began with the discovery of RPE65 variants and their association with Leber congenital amaurosis. The RPE65 protein is critical for the normal functioning of the visual phototransduction cascade. RPE65 gene knockout animal models were developed and showed similar diseased phenotypes to their human counterparts. Proof of concept studies were carried out in these animal models using subretinal RPE65 gene replacement therapy, resulting in improvements in various visual function markers including electroretinograms, pupillary light responses, and object avoidance behaviors. Positive results in animal models led to Phase 1 human studies using adeno-associated viral vectors. Results in these initial human studies also showed positive impact on visual function and acceptable safety. A landmark Phase 3 study was then conducted by Spark Therapeutics using a dose of 1.5 x1011 vector genomes after dose-escalation studies confirmed its efficacy and safety. Multi-luminance mobility testing was used to measure the primary efficacy endpoint due to its excellent reliability in detecting the progression of inherited retinal diseases. After the study met its primary endpoint, the Food and Drug Administration approved voretigene neparvovec (Luxturna®) for use in RPE65-associated inherited retinal diseases.
Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy. [2023]Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 1010 vg/eye resulted in transduction of 18%-85% of foveal cones. A Good Laboratory Practice (GLP) toxicology study established that IVT administration of ADVM-062 was well tolerated at doses that could potentially achieve clinically meaningful effect, thus supporting the potential of ADVM-062 as a one-time IVT gene therapy for BCM.
261st ENMC International Workshop: Management of safety issues arising following AAV gene therapy. 17th-19th June 2022, Hoofddorp, The Netherlands. [2023]Adeno-associated virus (AAV) gene therapies are demonstrating much promise in the area of neuromuscular disorders. There are now therapies in clinical trials or real-world use for several disorders including spinal muscular atrophy and Duchenne muscular dystrophy. However, there have been several concerning reports of serious adverse events, including deaths. Reporting and monitoring of these is not consistent between trials. Therefore, a group of clinicians, investigators, industry and patient representatives met the weekend of 17th-19th June 2022 to discuss safety issues arising from the use of these therapies. The group shared information on safety events across a spectrum of AAV gene therapy products, both in clinical trials and commercial use. Patterns of serious adverse events were identified and the group discussed methods of identification and management of these as well as new ways of improving information sharing across industry in order to improve the safety of these promising treatments.
Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration. [2022]Alternative splicing of nucleoredoxin-like 1 (Nxnl1) results in 2 isoforms of the rod-derived cone viability factor. The truncated form (RdCVF) is a thioredoxin-like protein secreted by rods that promotes cone survival, while the full-length isoform (RdCVFL), which contains a thioredoxin fold, is involved in oxidative signaling and protection against hyperoxia. Here, we evaluated the effects of these different isoforms in 2 murine models of rod-cone dystrophy. We used adeno-associated virus (AAV) to express these isoforms in mice and found that both systemic and intravitreal injection of engineered AAV vectors resulted in RdCVF and RdCVFL expression in the eye. Systemic delivery of AAV92YF vectors in neonates resulted in earlier onset of RdCVF and RdCVFL expression compared with that observed with intraocular injection using the same vectors at P14. We also evaluated the efficacy of intravitreal injection using a recently developed photoreceptor-transducing AAV variant (7m8) at P14. Systemic administration of AAV92YF-RdCVF improved cone function and delayed cone loss, while AAV92YF-RdCVFL increased rhodopsin mRNA and reduced oxidative stress by-products. Intravitreal 7m8-RdCVF slowed the rate of cone cell death and increased the amplitude of the photopic electroretinogram. Together, these results indicate different functions for Nxnl1 isoforms in the retina and suggest that RdCVF gene therapy has potential for treating retinal degenerative disease.
Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. [2016]Retinitis pigmentosa (RP) is a severe retinal disease characterized by a progressive degeneration of rod photoreceptors and a secondary loss of cone function. Here, we used CNGB1-deficient (CNGB1(-/-)) mice, a mouse model for autosomal recessive RP, to evaluate the efficacy of adeno-associated virus (AAV) vector-mediated gene therapy for the treatment of RP. The treatment restored normal expression of rod CNG channels and rod-driven light responses in the CNGB1(-/-) retina. This led to a substantial delay of retinal degeneration and long-term preservation of retinal morphology. Finally, treated CNGB1(-/-) mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this study holds promise for the treatment of rod channelopathy-associated retinitis pigmentosa by AAV-mediated gene replacement.