Project description
Oligonucleotide therapy for a rare neurodevelopmental disorder
Antisense oligonucleotides (ASOs) are synthetic single-stranded nucleic acid molecules designed to target specific RNA sequences. When ASOs bind to their intended targets, they can induce RNA degradation, inhibit protein synthesis or modulate RNA splicing. ASOs are being investigated as potential therapeutic agents for a variety of diseases, particularly those with a genetic basis. The ERC-funded FusionASO project aims to develop an ASO-based intervention for Wiedemann-Steiner syndrome (WSS), a neurodevelopmental disorder for which no treatment exists. The research team will target an RNA that, when targeted, can change the levels of KMT2A implicated in WSS. The approach is based on recent discoveries showing that such a targeting approach can boost the expression of helpful genes in the brain, thereby mitigating the clinical manifestations of WSS.
Objective
There is an immense interest in RNA therapeutics for a wide variety of health conditions. Neurodevelopmental disorders (NDDs), which mostly have no available treatments or cures, affect millions of children and adults across Europe, and are estimated to account for as much as 1-3% of the total EU healthcare expenditure. Wiedemann-Steiner Syndrome (WSS) is an NDD that currently has no available treatment and is not amenable to traditional gene therapy approaches.
Antisense oligonucleotides (ASOs) are a clinically proven way to modulate gene expression, in particularly in the central nervous system. ASOs are almost exclusively used for reduction of gene expression or altering RNA splicing, but these are relevant only in a subset of conditions. Many neurological diseases are caused by haploinsufficiency, in which the patient has one wild-type copy of the gene, but it is not sufficient for normal cellular function. ASO-based approaches for up-regulating haploinsufficient gene expression are sought in many cases, but existing methods, such as those focused on blocking microRNA target sites are often of limited efficacy.
In our ERC project, we made an intriguing observation that blocking specific regulatory motifs in the last exon of the CHASERR long noncoding RNAs leads to up-regulation of the downstream CHD2 gene through the formation of a fusion transcript between the two genes. We found that this approach can be translated for the up-regulation of CHD2 in vivo and alleviate disease-relevant phenotypes. In this PoC, we aim to extend this novel concept to WSS and explore and demonstrate the technical viability and commercial potential of targeting the ATP5MG pre-mRNA with specific ASOs to induce fusion formation with KMT2A (MLL1), thereby developing a potential new treatment for WSS. This project will not only advance the scientific understanding and therapeutic potential of this technology but also assess its market readiness and commercial feasibility.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-POC
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7610001 Rehovot
Israel
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