RNA Fusion-Inducing Antisense Oligonucleotides as a Treatment for Wiedemann-Steiner Syndrome

Descripción del proyecto

Tratamiento con oligonucleótidos para un trastorno raro del desarrollo neurológico

Los oligonucleótidos de antisentido (OAS) son moléculas sintéticas de ácido nucleico monocatenario diseñadas para unas secuencias de ARN específicas. Cuando los OAS se unen a sus objetivos previstos, pueden inducir la degradación del ARN, inhibir la síntesis de proteínas o modular el empalme del ARN. Se están investigando los OAS como posibles agentes terapéuticos para varias enfermedades, particularmente aquellas con base genética. El equipo del proyecto FusionASO, financiado por el CEI, tiene como objetivo desarrollar una intervención basada en ASO para el síndrome de Wiedemann-Steiner (WSS, por sus siglas en inglés), un trastorno del desarrollo neurológico para el que no existe un tratamiento. El equipo de investigación se centrará en un ARN que, cuando se lo selecciona, puede cambiar los niveles de KMT2A implicados en el WSS. El método se basa en descubrimientos recientes que muestran que dicho enfoque selectivo puede aumentar la expresión de los genes útiles en el encéfalo, mitigando así las manifestaciones clínicas del WSS.

Objetivo

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.