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

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”.