The expanding application of antisense oligonucleotides to neurodegenerative diseases

Abstract

Despite investment of billions of research dollars, neurodegenerative diseases have been largely resistant to therapeutics development because of incomplete understanding of molecular basis of disease, paucity of disease proximal targets, the complexity and relative inaccessibility of the nervous system, and lack of drug technologies that can directly target known genetic causes of disease.In recent decades, the JCI has published key preclinical advances highlighting the potential of DNA and RNA targeting therapeutics to be both safely delivered to the CNS and tackle the most proximal causes of neurogenetic disease.Two antisense oligonucleotides (ASOs) are now approved for the treatment of patients with the degenerative motor neuron diseases spinal muscular atrophy (SMA) and familial amyotrophic lateral sclerosis (ALS).Systemically delivered ASOs are also approved for Duchenne muscular dystrophy and familial amyloid neuropathy.Many others are in preclinical and clinical development in hopes that this therapeutic technology can be applied to a multitude of neurological diseases.Cerebrospinal fluid-delivered ASOs distribute to the CNS