Natural History of PRPF31 Mutation-Associated Retinal Dystrophy

A Natural History and Outcome Measure Discovery Study of PRPF31 Mutation-Associated Retinal Dystrophy

The purpose of this study is to characterize the natural history through temporal systemic evaluation of subjects identified with PRPF31 mutation-associated retinal dystrophy, also called retinitis pigmentosa type 11, or RP11.

Assessments will be completed to measure and evaluate structural and functional visual changes including those impacting patient quality of life associated with this inherited retinal condition and observing how these changes evolve over time.

Study Overview

• Status: Active, not recruiting
• Conditions: Retinitis Pigmentosa; Eye Diseases, Hereditary; Retinal Dystrophies; Retinal Dystrophy Rod; Retinal Dystrophy Rod Progressive

Detailed Description

This is a multi-center, longitudinal, prospective observational natural history study of participants with a molecularly confirmed mutation in PRPF31. Approximately 50 participants (100 eyes) at approximately 5 sites will be enrolled into a uniform protocol for follow-up and evaluations. Each participant's medical record will be reviewed for historical information, and clinical data will be recorded in a secure database. Natural history data will be collected prospectively and will include ophthalmic exams, imaging studies, electrophysiological testing, functional mobility evaluations, and questionnaires. Assessments will be conducted in a standardized protocol every 16 weeks ± 4 weeks for the first year and then every 24 weeks ± 4 weeks for up to approximately 4 years after each participant's baseline visit (Visit 2).

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

Study Locations

• Australia
  • East Melbourne, Australia
    • Centre For Eye Research Australia (CERA) - Retinal Gene Therapy Unit
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Lions Eye Institute
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan Kellogg Eye Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University - Casey Eye Institute
  • Texas
    • Dallas, Texas, United States, 75321
      • Retina Foundation of the Southwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of approximately 50 participants (100 eyes) with a genetically confirmed PRPF31 mutation.

Description

Inclusion Criteria:

Participants must meet all of the following in order to be enrolled into the study:

1. Male or female, ≥ 10 years of age at baseline (Visit 2).
2. Have a clinical and molecular diagnosis of PRPF31 mutation-associated retinal dystrophy.
3. If ≥ 18 years of age, understand the language of the informed consent and are willing and able to provide written informed consent prior to any study procedures. If < 18 years of age, are willing to assent to study participation in writing and have a legally authorized representative provide written informed consent on your behalf.
4. Are willing to comply with the instructions and attend all scheduled study visits.

Exclusion Criteria:

Participants or, in the case of ocular-specific criteria, individual eyes with any of the following will not be allowed to participate in this study:

1. Have any uncontrolled systemic disease that, in the opinion of the Investigator, would preclude participation in the study (e.g., infection, uncontrolled elevated blood pressure, cardiovascular disease, or glycemic control issues) or put the participant at risk due to study procedures.
2. Have mutations in genes that cause autosomal dominant retinitis pigmentosa (adRP), X-linked retinitis pigmentosa (XLRP), or presence of biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than PRPF31 mutations.
3. Have used anti-vascular endothelial growth factor (VEGF) agents or corticosteroid injections or implants.
4. Have had Ozurdex® implants placed within 3 months or Retisert® or Iluvien® implants placed within 3 years prior to Visit 2.
5. Within 3 months prior to Visit 2, have undergone any vitreoretinal surgery (scleral buckle, pars plana vitrectomy, retrieval of a dropped nucleus or intraocular lens, radial optic neurotomy, sheathotomy, cyclodestructive procedures or multiple filtration surgeries [2 or more], etc.) or any other ocular surgery.
6. Have ocular media opacity or poor pupillary dilation that prohibits quality ophthalmic evaluation or photography.
7. Have used any investigational drug or device within 90 days or 5 estimated half-lives of Visit 2, whichever is longer, or plan to participate in another study of drug or device during the study period.
8. Have received any prior cell or gene therapy for a retinal condition.
9. Have a history of illicit drug use or alcohol dependency.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Vision Cohort 1; Score of ≥ 54 ETDRS letters read and a VF diameter ≥ 10 degrees in every meridian of the central field
Vision Cohort 2; Score of ≥ 35 ETDRS letters read and a VF diameter < 10 degrees in any meridian of the central field
Vision Cohort 3; Score of < 35 ETDRS letters read

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Best Corrected Visual Acuity (BCVA)	BCVA letter score utilizing ETDRS (Early Treatment Diabetic Retinopathy Study) or BRVT (Berkeley Rudimentary Vision Test) for patients not able to see letters	Baseline through Year 4
Change in Best Corrected Low Luminance Visual Acuity (LLVA)	Best corrected LLVA letter score measured using the ETDRS charts and a special light filter lens	Baseline through Year 4
Change from Baseline in Retinal Thickness	Retinal thickness is measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center	Baseline through Year 4
Change from Baseline in Ellipsoid Zone (EZ) Area	Change in EZ area measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center	Baseline through Year 4
Change from Baseline in Ellipsoid Zone (EZ) Volume	Change in EZ volume measured using spectral domain optical coherence tomography (SD-OCT), as measured by the central reading center	Baseline through Year 4
Change from Baseline in Visual Field Sensitivity	Visual field sensitivity measured by static perimetry with topographic analysis-Hill of Vision conducted by the central reading center	Baseline through Year 4
Change from Baseline in Mean Macular Sensitivity	Mean macular sensitivity measured on guided microperimetry	Baseline through Year 4
Change from Baseline in Fixation Stability	Fixation stability as measured by Macular Integrity Assessment (MAIA) microperimeter	Baseline through Year 4
Change from Baseline in Full Field Retinal Sensitivity	Dark-adapted visual sensitivity via full-field stimulus threshold (FST) measurement	Baseline through Year 4
Change from Baseline in Electrical response	Electrical response measured using Full-field electroretinogram (ERG) with specific stimuli	Baseline through Year 4
Characterization of Changes of the Retina with Fundus Photography	Abnormalities captured by fundus photography	Baseline through Year 4
Change from Baseline in Area of Fundus Autofluorescence (FAF)	Area of hypo-autofluorescence captured by fundus autofluorescence (FAF)	Baseline through Year 4
Change from Baseline in Functional Vision	Functional vision is measured with a functional mobility course (Ora-VNC™) score	3 times prior to Month 4
Change in Patient Reported Outcome Measures using Michigan Retinal Degeneration Questionnaire (MRDQ)	Responses on the MRDQ, a validated patient reported outcomes measure designed in accordance with U.S. FDA guidelines, specifically for conditions of inherited retinal degeneration (IRDs)	Baseline through Year 4
Change in Patient Reported Outcome Measures using Patient Global Impression of Severity (PGI-S) scale	Responses on the PGI-S to assess severity of the patient's condition	Baseline through Year 4
Change in Patient Reported Outcome Measures using Patient Global Impression of Change (PGI-C) scale	Responses on the PGI-C to assess change of the patient's condition	Baseline through Year 4
Genomic Analysis for Study Eligibility	Whole exome genomic analysis	Screening
Ocular Adverse Events (AEs)	Frequency of ocular adverse events (AEs)	Screening through Year 4

Collaborators and Investigators

• Sponsor: PYC Therapeutics
• Investigators: Study Chair: Sreenivasu Mudumba, PhD, PYC Therapeutics

Publications and helpful links

General Publications

• Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. doi: 10.1016/S0140-6736(06)69740-7.
• Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell. 2001 Aug;8(2):375-81. doi: 10.1016/s1097-2765(01)00305-7.
• Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011 Jun;12(4):238-49. doi: 10.2174/138920211795860107.
• Rio Frio T, Wade NM, Ransijn A, Berson EL, Beckmann JS, Rivolta C. Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay. J Clin Invest. 2008 Apr;118(4):1519-31. doi: 10.1172/JCI34211.
• Sullivan LS, Bowne SJ, Seaman CR, Blanton SH, Lewis RA, Heckenlively JR, Birch DG, Hughbanks-Wheaton D, Daiger SP. Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4579-88. doi: 10.1167/iovs.06-0440.
• Venturini G, Rose AM, Shah AZ, Bhattacharya SS, Rivolta C. CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS Genet. 2012;8(11):e1003040. doi: 10.1371/journal.pgen.1003040. Epub 2012 Nov 8.
• Wheway G, Douglas A, Baralle D, Guillot E. Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy. Exp Eye Res. 2020 Mar;192:107950. doi: 10.1016/j.exer.2020.107950. Epub 2020 Jan 31.
• Food and Drug Administration. Rare Diseases: Natural History Studies for Drug Development. Draft Guidance for Industry 2019. https://www.fda.gov/media/122425/download

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2022
• Primary Completion (Estimated): September 9, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: September 8, 2022
• First Submitted That Met QC Criteria: October 5, 2022
• First Posted (Actual): October 10, 2022

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Retinitis Pigmentosa; Retinal Dystrophy; PRPF31; Retinitis Pigmentosa Type 11; RP11; PRPF31 Mutation-Associated Retinal Dystrophy
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Eye Diseases; Retinal Diseases; Retinal Degeneration; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Retinitis Pigmentosa; Retinal Dystrophies; Eye Diseases, Hereditary
• Other Study ID Numbers: VP001-CL001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No