Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models

Abstract

Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy.

Protein production is an early biomarker for RNA‐targeted therapies

“…Previous data suggest this limitation may be due to the drug delivery paradigm in these experiments. The current study used a single bolus injection of ASO in rodent models while previous studies that observed total target protein lowering in CSF after ASO treatment in nonhuman primate models were performed with multiple intrathecal ASO injections 10, 21. Additionally, both transgenic animal models used here express wild‐type forms of the target protein.…”

“…ASOs that recruit RNase‐H to degrade target mRNA and an inactive, control ASO with no sequence specificity were provided by Ionis Pharmaceuticals 10, 21 (Fig. 1).…”

“…P  < 0.05 was determined significant. Based on previous results,10, 21 a cutoff of 50% target mRNA reduction relative to the mean mRNA levels in inactive ASO‐treated animals was used as inclusion criteria for subsequent analysis. In CSF analysis, samples were excluded if blood contamination was visibly present or if the volume of CSF collected was less than 75  μ L. For relative quantification, samples were normalized to a single sample in each experiment from the inactive ASO treatment group.…”

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.…”