Therapeutics

ION464

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Overview

Name: ION464
Synonyms: BIIB101, IONIS-BIIB6Rx
Therapy Type: DNA/RNA-based
Target Type: alpha-synuclein
Condition(s): Multiple System Atrophy
U.S. FDA Status: Multiple System Atrophy (Phase 1)
Company: Biogen, IONIS Pharmaceuticals

Background

ION464 is an antisense oligonucleotide targeting α-synuclein mRNA to block production of the protein. It is being developed as a potential therapy for Parkinson’s disease, multiple system atrophy, and related synucleinopathies. In these diseases, accumulation of aberrant forms of α-synuclein leads to neurodegeneration. By reducing synthesis of α-synuclein, ION464 is intended to prevent the toxicity of mutant or misfolded forms of the protein.

In preclinical models, Ionis’ α-synuclein ASOs inhibited protein production, and prevented neuronal death after exposure to toxic α-synuclein fibrils (Luna et al., 2018). The ASO similarly reduced α-synuclein production, and prevented development of pathology and motor deficits after injection of toxic fibrils in rodent models. When tested in a treatment paradigm, the ASO reduced levels of pre-existing α-synuclein pathology, and neuron loss. In nonhuman primates, intrathecal delivery of the ASO resulted in lowering of α-synuclein protein in brain and spinal cord (Cole et al., 2021). In another study involving a similar injection of preformed α-synuclein fibrils in mice, the ASO decreased α-synuclein protein levels and pathology, but was also associated with a decline in body weight and motor impairments (Boutros et al., 2021).

Findings

In July 2022, Ionis began a Phase 1 study of ION464 in 40 spinal muscular atrophy patients. Participants must have loss of dopamine nerve terminals detected on a DaTscan, and cognitive dysfunction. The first part of the study involves intrathecal injection of multiple ascending doses or placebo at regulator intervals over 12 weeks. In a second part, participants will receive a set dose multiple times over 72 weeks. The primary outcome is safety. Secondary outcomes include measures of CSF α-synuclein and blood ASO levels. The trial, at 10 sites in Austria, France, Germany, and the U.K., is expected to be complete by December 2025.

For details on ION464 trials, see clinicaltrials.gov.

Last Updated: 17 Jan 2023

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References

Paper Citations

  1. Luna E, Decker SC, Riddle DM, Caputo A, Zhang B, Cole T, Caswell C, Xie SX, Lee VM, Luk KC. Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta Neuropathol. 2018 Jun;135(6):855-875. Epub 2018 Mar 3 PubMed.
  2. Cole TA, Zhao H, Collier TJ, Sandoval I, Sortwell CE, Steece-Collier K, Daley BF, Booms A, Lipton J, Welch M, Berman M, Jandreski L, Graham D, Weihofen A, Celano S, Schulz E, Cole-Strauss A, Luna E, Quach D, Mohan A, Bennett CF, Swayze EE, Kordasiewicz HB, Luk KC, Paumier KL. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease. JCI Insight. 2021 Mar 8;6(5) PubMed.
  3. Boutros SW, Raber J, Unni VK. Effects of Alpha-Synuclein Targeted Antisense Oligonucleotides on Lewy Body-Like Pathology and Behavioral Disturbances Induced by Injections of Pre-Formed Fibrils in the Mouse Motor Cortex. J Parkinsons Dis. 2021;11(3):1091-1115. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading