Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identifiedHTTsingle-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutatedHTTmight have therapeutic effects on HD-mediated cognitive impairments.

A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system

“…Many technologies are being explored for gene modulation in the CNS, including adenoassociated virus (AAV) and ASOs 4,41,42 . AAV delivered by intra-parenchymal injections efficiently silenced HTT in minipig, sheep, and NHP 41,43,44 .…”

“…ASOs have enabled ~50% decrease of soluble mutant HTT in the CSF of patients following monthly intrathecal injections 45 . However, ASO delivery to deep brain structures is limited 4 , with no significant HTT silencing observed in NHP caudate after multiple injections 42 .…”

Antisense oligonucleotides extend survival of prion-infected mice

“…protein in the brain and are being advanced preclinically and clinically for several other neurodegenerative diseases (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These short (17-20 base) single-stranded oligonucleotides, chemically modified for pharmacokinetic stability, are capable of impacting disease biology through specific modulation of complementary target RNAs (30,31), including RNAse H-dependent degradation (32)(33)(34).…”

Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome

“…Antisense oligonucleotides (ASOs) hybridize by Watson–Crick base pairing to mRNAs, leading to degradation by ribonuclease H, inhibition of translation, or altered splicing. Dominant disorders can be treated with allele‐specific ASOs that specifically target the mutant transcript, or with non–allele‐specific ASOs that reduce both mutant and wild‐type transcript . The application of ASO therapy to neurological disorders is receiving increasing attention, and the US Food and Drug Administration has recently approved treatment for spinal muscular atrophy that uses intrathecal administration of an ASO at 6‐month intervals .…”

“…Dominant disorders can be treated with allele-specific ASOs that specifically target the mutant transcript, or with non-allele-specific ASOs that reduce both mutant and wild-type transcript. 12,13 The application of ASO therapy to neurological disorders is receiving increasing attention, [14][15][16] and the US Food and Drug Administration has recently approved treatment for spinal muscular atrophy that uses intrathecal administration of an ASO at 6-month intervals. 17 The goal of the current work was to evaluate ASO therapy for SCN8A encephalopathy.…”