NU 2021-058
INVENTORS
Evangelos Kiskinis* Juan Alberto Ortega Cano Marco Boccitto
SHORT DESCRIPTION
Design of an RNA-based oligonucleotide that protects from dipeptide repeat protein toxicity for the treatment of ALS and FTD.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases without effective, long-term treatments. The most prevalent genetic cause for both diseases is a repeat expansion mutation in the C9orf72 gene causing production of arginine-rich dipeptide repeat proteins (DPRs). These DPRs bind directly to native ribosomal RNA, disrupting ribosomal homeostasis and inhibiting protein translation. DPR-rRNA binding is a toxic driver of neuronal dysfunction and degeneration, characteristic of ALS and FTD. Currently, there exists a need for disease-modifying and curative drugs in ALS and FTD which target the underlying genetic causes over the symptomatic treatments that currently dominate the market.
ABSTRACT
Northwestern University researchers have designed a modified rRNA “bait” oligonucleotide which binds one of the most toxic DPRs (poly-GR). This “bait” oligonucleotide prevents the binding of toxic proteins to ribosomal RNA. Use of this therapeutic strategy reduces poly-GR-associated ribosomal deficits and ameliorates poly-GR toxicity. In ALS patient motor neurons with poly-GR aggregates, treatment with “bait” oligonucleotides reduce cell death by 25%. In Drosophilia, treatment with the “bait” oligonucleotide at the larval stage increased survival to adulthood. This “bait” oligonucleotide is a promising candidate for protection against C9orf72 pathophysiological mechanisms, addressing a primary genetic cause of disease development.
APPLICATIONS
ADVANTAGES
Unique therapeutic target
Custom designed bait oligonucleotide allows for modifications (improve stability, enhance binding, etc.)
PUBLICATION
Ortega J. et. al. (2023) Clip-Seq Analysis Enables the Design of Protective Ribosomal RNA Bait Oligonucleotides Against C9orf72 ALS/FTD Poly-GR Pathophysiology. Science Advances 9(45): eadf7997.
IP STATUS
US and international patent applications have been filed.
INVO CONTACT
Michael Fiske, PhD Invention Manager (e) michael.fiske@northwestern.edu
Treatment of patient motor neurons with RNA-based oligonucleotide inhibits toxic effects in mutant C9orf72 ALS, increasing survival compared to control and scramble-bait treated motor neurons.