RNA Fusion-Inducing Antisense Oligonucleotides as a Treatment for Wiedemann-Steiner Syndrome
| Title | RNA Fusion-Inducing Antisense Oligonucleotides as a Treatment for Wiedemann-Steiner Syndrome |
|---|---|
| Acronym | FusionASO |
| Start date | 2025-06-01 |
| End date | 2027-11-30 |
| Sponsor | European Research Council - Proof of Concept (ERC-PoC) |
| Institution | Weizmann Institute of Science |
Associated cell lines
Project Description
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 people 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. 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. Antisense oligonucleotides (ASOs), a clinically proven method to modulate gene expression, are particularly effective in the central nervous system. 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. This approach can be translated for the up-regulation of CHD2 in vivo and alleviate disease-relevant phenotypes. In this project we aim to extend this concept to WSS by, developing a new treatment for WSS. This approach offers significant commercial potential as it provides a versatile platform for treating not only WSS but also other haploinsufficient disorders lacking effective therapies.