Oligonucleotide therapeutics in neurodegenerative diseases

Abstract

Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.

Keywords: RNA therapeutics; antisense oligonucleotides; neurodegenerative diseases.

Figure 1.

Common types of RNA-targeted therapeutics.

Figure 2.

ASO modifications and action of ASOs supporting RNase H1 activity. a) Commonly used ASO modifications. b) Typical action of an ASO supporting RNase H1 activity. The structure of the gapmer ASO is shown, where all positions are phosphorothioate (PS) modified and 5 bp on each flank are also 2′-MOE modified. Following cellular uptake the ASO engages the target and RNase H1 is recruited and cleaves the RNA target opposite of the PS ASO bps. The cleaved RNAs are then eliminated by nonsense mediated decay (NMD).

Figure 3.

ATXN2 ASO7 improved SCA2 mouse phenotypes. a) SCA2 mice (Pcp2-ATXN2-Q127) were treated ICV with ASO7 at 8 weeks of age then motor behavior was tested on the accelerating rotarod. Values shown are means and standard deviations for three daily trials per week of testing (NS = non-significant; * = p < 0.05; ** = p < 0.01). b) At the endpoint of the experiment in A, Purkinje cell firing frequencies were determined in using extracellular recordings from acute cerebellar slices. Normal firing frequencies were recorded from ASO7 treated mice. Firing frequency distributions are shown on the left and representative firing traces for 1s of recording on the right.