Gene Therapy with SPVN06 for Cone-Rod Dystrophy

(PRODYGY Trial)

Recruiting at 4 trial 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. ^{1 2 3 4 5}

What 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. ^{6 7 8 9 10}

What 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. ^{1 2 9 11 12}

Eligibility 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

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

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

Treatment Details

Interventions

• SPVN06 (Gene Therapy)

Trial Overview 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.

Participant Groups

Group I: Step 2 : SPVN06 Dose Recommended 2 Experimental Treatment 1 Intervention

Participants will receive a single subretinal injection of SPVN06 recommended dose 2 on Day 0

Group II: Step 2 : SPVN06 Dose Recommended 1 Experimental Treatment 1 Intervention

Participants will receive a single subretinal injection of SPVN06 recommended dose 1 on Day 0

Group III: Step 1 : SPVN06 dose 3 Experimental Treatment 1 Intervention

Participants will receive a single subretinal injection of SPVN06 Dose 3 on Day 0

Group IV: Step 1 : SPVN06 dose 2 Experimental Treatment 1 Intervention

Participants will receive a single subretinal injection of SPVN06 Dose 2 on Day 0

Group V: Step 1 : SPVN06 dose 1 Experimental Treatment 1 Intervention

Participants will receive a single subretinal injection of SPVN06 Dose 1 on Day 0.

Group VI: Step 2 : Control group Active Control 1 Intervention

Who Is Running the Clinical Trial?

SparingVision

Lead Sponsor

Trials

3

Recruited

230+

Findings from Research

Gene therapy using AAV vectors successfully restored the expression of the CNGB1a protein in a mouse model of retinitis pigmentosa, leading to the formation of functional CNG channels and preservation of retinal structure.

The treated mice showed significant improvements in retinal function and behavior, indicating that this gene therapy approach could be a promising treatment for rod channelopathy-associated retinitis pigmentosa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. Koch, S., Sothilingam, V., Garcia Garrido, M., et al.[2012]

Gene therapy using AAV5 or AAV8 vectors in RPGRIP1-deficient dogs significantly improved photoreceptor survival and cone function, achieving 18-72% of normal vision levels for up to 24 months after treatment.

The therapy not only preserved rod function in four out of five treated dogs but also maintained their ability to see in both bright and dim light, indicating a strong potential for similar treatments in humans with cone-rod dystrophies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. Lhériteau, E., Petit, L., Weber, M., et al.[2021]

In a phase 3 trial involving 31 participants with RPE65-mediated inherited retinal dystrophy, the gene therapy voretigene neparvovec significantly improved functional vision, as measured by multi-luminance mobility testing (MLMT), with an average improvement of 1.8 light levels compared to only 0.2 in the control group.

The treatment was found to be safe, with no serious adverse events related to the therapy, and 65% of participants in the intervention group achieved maximum improvement at the lowest luminance level tested, indicating a strong potential for restoring vision in previously untreatable cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Russell, S., Bennett, J., Wellman, JA., 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]

Gene therapy using AAV2/8(Y733F)-Rho-Pde6α can effectively rescue cone photoreceptor function in a pre-clinical model of retinitis pigmentosa even after the onset of disease, specifically when treatment is administered at post-natal day 21.

This approach demonstrates potential for clinical application in human patients diagnosed with mid-stage retinitis pigmentosa, as it can restore some visual function when delivered after significant photoreceptor degeneration has already occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa. Wert, KJ., Sancho-Pelluz, J., Tsang, SH.[2021]

The study assessed the safety of a gene therapy using a recombinant adeno-associated virus vector (rAAV2-CB-hRPE65) in 12 patients (8 adults and 4 children) with retinal degeneration due to RPE65 mutations, finding no serious treatment-related adverse events after 2 years of follow-up.

Improvements in visual function were observed in 9 out of 12 patients, with the most significant gains in younger patients who had better baseline visual acuity, indicating potential efficacy of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Weleber, RG., Pennesi, ME., Wilson, DJ., et al.[2017]

In a follow-up phase 1 trial involving 11 patients aged 11-46 years, the subretinal injection of AAV2-hRPE65v2 into the contralateral eye showed no serious adverse events related to the treatment, indicating a favorable safety profile.

Most patients experienced significant improvements in mobility and light sensitivity in the newly treated eye, with effects lasting up to 3 years, demonstrating the efficacy of AAV2-hRPE65v2 as a gene therapy for inherited retinal dystrophy caused by RPE65 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Bennett, J., Wellman, J., Marshall, KA., et al.[2022]

Subretinal gene therapy targeting the RPE65 gene has shown significant improvements in visual function in both animal models and initial human trials, leading to the FDA approval of voretigene neparvovec (Luxturna®) for treating RPE65-associated inherited retinal diseases.

The Phase 3 study demonstrated that the therapy was effective and safe, using reliable mobility testing to confirm its efficacy, which supports its use as a treatment option for patients with this genetic condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence. Gao, J., Hussain, RM., Weng, CY.[2020]

ADVM-062, a gene therapy vector administered via a single intravitreal injection, effectively transduced cone photoreceptors in gerbils and elicited a response to long-wavelength light, indicating its potential efficacy for treating blue cone monochromacy (BCM).

In non-human primates, doses of ADVM-062 ≥3 × 10^10 vg/eye successfully transduced 18%-85% of foveal cones, and a toxicology study confirmed that the treatment was well tolerated, supporting its safety for potential human use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy. Hanna, K., Nieves, J., Dowd, C., et al.[2023]

Adeno-associated virus (AAV) gene therapies show great potential for treating neuromuscular disorders like spinal muscular atrophy and Duchenne muscular dystrophy, but there have been serious safety concerns, including reports of deaths.

A recent meeting of clinicians and industry representatives highlighted the need for better reporting and monitoring of adverse events associated with AAV therapies to enhance patient safety and improve information sharing across trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

261st ENMC International Workshop: Management of safety issues arising following AAV gene therapy. 17th-19th June 2022, Hoofddorp, The Netherlands. Servais, L., Horton, R., Saade, D., et al.[2023]

Gene therapy using adeno-associated virus (AAV) successfully restored normal function of rod photoreceptors in CNGB1-deficient mice, a model for retinitis pigmentosa, leading to delayed retinal degeneration.

Treated mice showed significant improvements in vision-related behaviors compared to untreated mice, indicating the potential efficacy of this gene therapy approach for treating rod channelopathy-associated retinitis pigmentosa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. Michalakis, S., Koch, S., Sothilingam, V., et al.[2016]

References

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

Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. [2012]

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

Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. [2021]

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

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]

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. England pubmed.ncbi.nlm.nih.gov

Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa. [2021]

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

Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. [2017]

7. England pubmed.ncbi.nlm.nih.gov

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]

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

Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence. [2020]

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

Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy. [2023]

10. England pubmed.ncbi.nlm.nih.gov

261st ENMC International Workshop: Management of safety issues arising following AAV gene therapy. 17th-19th June 2022, Hoofddorp, The Netherlands. [2023]

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

Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration. [2022]

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

Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. [2016]