Periodic Reporting for period 1 - ProgRet (European Training Program to Understand, Diagnose and Treat Autosomal Dominant Retinal Diseases)
Período documentado: 2024-01-01 hasta 2025-12-31
ProgRET is a multidisciplinary and intersectoral European training network focusing on the mechanisms, diagnosis and therapy of dominantly inherited retinal diseases (IRD). IRD represent a major cause of blindness, affecting 350,000 people in Europe. IRD have long been considered incurable, however major advances have led to groundbreaking new treatments. ProgRET addresses the most important challenges in the IRD field relate to an unsolved genetic diagnosis, unknown disease mechanisms and gene therapy development for autosomal dominant IRD (adIRD), representing 25–40% of all IRD cases. We have demonstrated an emerging role for splicing factors, structural variants and non-coding defects in patients with adIRD, and developed novel disease models and gene therapies for adIRD.
ProgRET aims to dissect adIRD mechanisms using retinal stem cell and aquatic animal models, to advance adIRD diagnostics using a single-molecule multiomics framework, and to develop innovative treatments based on RNA therapy and CRISPR-genome editing. These challenges are tackled by integrating unique expertise and cutting-edge technology within ProgRET, including (multi)omics, bioinformatics, functional genomics, RNA biology, gene regulation, stem cell technology, retinal organoids, animal models, genome editing and gene therapy.
ProgRET aims to dissect adIRD mechanisms using retinal stem cell and aquatic animal models, to advance adIRD diagnostics using a single-molecule multiomics framework, and to develop innovative treatments based on RNA therapy and CRISPR-genome editing. These challenges are tackled by integrating unique expertise and cutting-edge technology within ProgRET, including (multi)omics, bioinformatics, functional genomics, RNA biology, gene regulation, stem cell technology, retinal organoids, animal models, genome editing and gene therapy.
Disease mechanisms and models.
The consortium established human stem-cell–derived retinal models, retinal organoids, and aquatic animal models to study aging and retinal degeneration. High-resolution 3D maps of chromatin (how DNA folds in cells) has been established and genome-wide profiles of gene activity and open chromatin have been generated across developmental stages and disease models. These data help pinpoint regulatory defects and splicing changes that may drive adIRD.
Advanced diagnostics.
ProgRET applies short- and long- read whole- genome sequencing multiomics to resolve unsolved IRD cases. Long-read sequencing has clarified complex structural variants and pathogenic changes missed by standard tests, raising the diagnostic yield. We are also piloting multiway 3D genome interaction methods to connect noncoding variants with their target genes, and contributed to international efforts mapping pathogenic variants in small nuclear RNA genes involved in splicing.
Therapeutic innovation.
Several complementary strategies are under development in this context:
1) Antisense oligonucleotides (ASOs) to selectively reduce toxic dominant transcripts or to lift translation in haploinsufficiency.
2) CRISPR prime/base editing to introduce protective edits that down-tune mutant allele expression without altering the healthy allele.
3) Allele-specific knockdown approaches for key adIRD genes.
Early assays in cell systems and retinal organoids show promising on-target effects, which is promising for further preclinical work.o ensure comparability between batches and lines.
The consortium established human stem-cell–derived retinal models, retinal organoids, and aquatic animal models to study aging and retinal degeneration. High-resolution 3D maps of chromatin (how DNA folds in cells) has been established and genome-wide profiles of gene activity and open chromatin have been generated across developmental stages and disease models. These data help pinpoint regulatory defects and splicing changes that may drive adIRD.
Advanced diagnostics.
ProgRET applies short- and long- read whole- genome sequencing multiomics to resolve unsolved IRD cases. Long-read sequencing has clarified complex structural variants and pathogenic changes missed by standard tests, raising the diagnostic yield. We are also piloting multiway 3D genome interaction methods to connect noncoding variants with their target genes, and contributed to international efforts mapping pathogenic variants in small nuclear RNA genes involved in splicing.
Therapeutic innovation.
Several complementary strategies are under development in this context:
1) Antisense oligonucleotides (ASOs) to selectively reduce toxic dominant transcripts or to lift translation in haploinsufficiency.
2) CRISPR prime/base editing to introduce protective edits that down-tune mutant allele expression without altering the healthy allele.
3) Allele-specific knockdown approaches for key adIRD genes.
Early assays in cell systems and retinal organoids show promising on-target effects, which is promising for further preclinical work.o ensure comparability between batches and lines.
ProgRET integrates single-molecule multiomics, long-read sequencing, and multiway chromatin conformation methods to understand gene regulation and expression in the retina and RPE, and to trace how noncoding or cryptic defects cause adIRD. In addition, the ProgRET consortium increased diagnostic yield in previously molecularly undiagnosed cases with the recent discovery of a novel snRNA-related dominant retinopathy as a striking example. In addition, it has established original therapeutic advanes (ASOs, base/prime editing) that can be used to rescue different dominant IRD mechanisms.
Training and capacity building
ProgRET delivers a structured programme of research skills (genomics, transcriptomics, stem cell technology, functional genomics, bioinformatics, gene therapy) and complementary skills (research integrity, science communication, project management, IP and entrepreneurship). Doctoral candidates rotate across academic and industrial environments through secondments, gaining a rare, fully translational perspective from mechanism to therapy.
Communication, dissemination, and exploitation
The project maintains a public website and active social media channels to explain IRD and share progress in accessible formats. Research outputs are disseminated at international meetings and through open publications; an exploitation and dissemination plan guides the translation of results and the protection of intellectual property when appropriate.
Expected longer-term impacts
ProgRET will deliver: (i) enhanced strategies to map the regulation of retina and RPE, and to model adIRD; (ii) improved diagnostic pipelines that capture complex and noncoding variants that underlie adRD; (iii) validated therapeutic strategies for diverse adIRD mechanisms; and (iv) a new generation of cross-sector scientists ready to accelerate innovation in vision research. Collectively, these advances aim to reduce time-to-diagnosis, innovate therapeutic options, and ultimately preserve vision for patients with IRD.
Training and capacity building
ProgRET delivers a structured programme of research skills (genomics, transcriptomics, stem cell technology, functional genomics, bioinformatics, gene therapy) and complementary skills (research integrity, science communication, project management, IP and entrepreneurship). Doctoral candidates rotate across academic and industrial environments through secondments, gaining a rare, fully translational perspective from mechanism to therapy.
Communication, dissemination, and exploitation
The project maintains a public website and active social media channels to explain IRD and share progress in accessible formats. Research outputs are disseminated at international meetings and through open publications; an exploitation and dissemination plan guides the translation of results and the protection of intellectual property when appropriate.
Expected longer-term impacts
ProgRET will deliver: (i) enhanced strategies to map the regulation of retina and RPE, and to model adIRD; (ii) improved diagnostic pipelines that capture complex and noncoding variants that underlie adRD; (iii) validated therapeutic strategies for diverse adIRD mechanisms; and (iv) a new generation of cross-sector scientists ready to accelerate innovation in vision research. Collectively, these advances aim to reduce time-to-diagnosis, innovate therapeutic options, and ultimately preserve vision for patients with IRD.