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

Descrizione del progetto

Terapia oligonucleotidica per un raro disturbo dello sviluppo neurologico

Gli oligonucleotidi antisenso (antisense oligonucleotides, ASO) sono molecole di acido nucleico sintetiche a filamento singolo progettate per bersagliare sequenze specifiche di RNA. Quando gli ASO si legano ai loro bersagli, possono indurre la degradazione dell’RNA, inibire la sintesi proteica o modulare lo splicing dell’RNA. Gli ASO sono oggetto di studio come potenziali agenti terapeutici per una varietà di malattie, in particolare quelle con una base genetica. Il progetto FusionASO, finanziato dal CER, mira a sviluppare un intervento basato sugli ASO per la sindrome di Wiedemann-Steiner (Wiedemann-Steiner syndrome, WSS), un disturbo dello sviluppo neurologico per il quale non esiste alcuna cura. Il team di ricerca punterà a un RNA che, una volta bersagliato, può modificare i livelli di KMT2A implicati nella WSS. L’approccio si basa su recenti scoperte che dimostrano come un simile approccio mirato possa aumentare l’espressione di geni utili nel cervello, attenuando così le manifestazioni cliniche della WSS.

Obiettivo

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.