Responsabile Scientifico

• SANTORO Claudio Ventura (DSS)

Partecipanti al progetto

• SANTORO Claudio Ventura (DSS)
• FOLLENZI Antonia (DSS)
• GIORDANO Mara (DSS)

Titolo del progetto

• PERTINENT- PhEnotyping ReTinitis pIgmeNtosa (RP11) modEls aNd effective Therapies

Ente finanziatore

• 
  MUR - Ministero dell'Università e Ricerca

Programma di finanziamento

• PRIN - Progetti di Ricerca di Rilevante Interesse Nazionale (dal 2020)

Bando di riferimento

• PRIN 2022 PNRR

Anno di presentazione del progetto

• 2022

Anno di approvazione del progetto

• 2023

Project ID / numero contratto

• P202285PPY_001

Durata del progetto

• 24 mesi

Inizio del progetto

• 30/11/2023

Fine del progetto

• 29/11/2025

Ente capofila

• UNIUPO - Universita Degli Studi del Università del Piemonte Orientale "Amedeo Avogadro"

Altri partner del progetto

• UNIMI - Università degli studi di Milano
• UNITO - Dipartimento di Scienze della Vita e Biologia dei Sistemi

Progetto approvato - Contributo unità di ricerca del Dipartimento

• €115.543,00

Sustainable Development Goals - Agenda 2030

Keyword

• Retinitis pigmentosa
• RNA-based therapy
• Gene-therapy
• Omics
• Haploinsufficiency
• Rare diseases

Stato del progetto

• Approvato

Abstract

• Retinitis Pigmentosa (RP) is the most common inherited retinal dystrophy (IRD), with a worldwide prevalence of approximately 1:4000 and affecting over 1.5 million patients worldwide (1). RP symptoms starts often during adolescence as nyctalopia and gradually progress to central vision loss and eventual blindness by the age of 40-50. As such, RP has a significant impact on patient’s life, with a high burden on patients, families and society. RP11 is a non-syndromic autosomal-dominant (AD) IRD caused by mutations in the PRPF31 gene encoding an essential spliceosome component. Most of the mutations are loss-of-function determining PRPF31 haploinsufficiency (HI). The pathogenic mechanisms are poorly defined, being altered ciliogenesis the most consistent defect observed in RP11 cell models (2). Due to the lack of animal models (3,4), Retinal Pigment Epithelium (RPE) and/or Retinal Organoids (ROs) derived from RP11 patient iPSCs, are the leading RP11 models (5) As HI, viral-based gene supplementation is considered the leading strategy for RP11 therapy. Despite the promising results (6,7), though, if and how PRPF31 overexpression impacts the middle-long term behavior of retina cells is still unknown. This is not trivial considering that: PRPF31 is an essential ubiquitous spliceosomal factor; minimal increases of wt allele expression are observed in asymptomatic carriers; mutation burden of somatic cells can impact iPSC-derived models. Based on these premises, PERTINENT project aims to build a knowledge-based platform to guide the development of appropriated therapies for PRPF31 HI in order to mitigate/avoid the potential health risks due to underrated effects of gene overexpression and/or somatic source for iPSC generation. To this goal, PERTINENT will define the evolution of omics phenotypes of cell models in a RP11 or control context. New and available data sets will be used as reference to assess, monitor over time and compare the impact of two alternative gene-augmentation strategies: one based on the ectopic expression of PRPF31 transgene, the other based on the physiological increase of PRPF31 protein mediated by SINEUP molecules. PERTINENT will also provide best practice points to establish iPSC cell models. In conclusion, PERTINENT will match the requirements with the Strategic Topic of Human Wellbeing in relation to the Cluster 1.3 "....to tackle...rare diseases and reduce the disease burden effectively thanks to better under standing of diseases and using more effective health technologies”.