2026 年 43 巻 3 号 p. 255-259
Nucleic acid therapeutics represent a rapidly advancing class of middle–molecule drugs characterized by high sequence specificity and accelerated drug development timelines. Alongside antibody therapeutics and gene therapy, they have emerged as a major therapeutic modality, particularly in neuromuscular and neurological disorders. The clinical success of nusinersen for spinal muscular atrophy, approved globally since 2016, demonstrated for the first time that intrathecally delivered antisense oligonucleotides (ASOs) can act as disease–modifying therapies for central nervous system (CNS) disorders. More recently, tofersen for SOD1–associated amyotrophic lateral sclerosis (ALS) further expanded the clinical application of nucleic acid therapeutics in neurodegenerative diseases.
Despite these successes, CNS–targeted nucleic acid drug development faces significant challenges. Several ASOs targeting C9orf72–associated ALS and Huntington's disease failed to demonstrate clinical efficacy, highlighting a critical trade–off between efficacy and dose–limiting neurotoxicity. Accumulating evidence indicates that CNS neurotoxicity associated with intrathecal nucleic acid therapeutics comprises two mechanistically distinct entities : acute–onset and late–onset neurotoxicity. Acute neurotoxicity appears shortly after administration and resolves rapidly, whereas delayed neurotoxicity emerges days to weeks later and progresses gradually.
Recent mechanistic studies revealed that acute neurotoxicity is mediated by extracellular effects of nucleic acids, particularly guanine–dependent inhibition of AMPA receptor function leading to reductions in intracellular calcium levels. In contrast, late–onset neurotoxicity arises from intracellular mechanisms, including aberrant interactions with nuclear paraspeckle proteins, resulting in their abnormal localization and subsequent neuronal cell death.
Based on these molecular insights, novel nucleic acid chemical modifications have been developed to mitigate neurotoxicity while maintaining therapeutic efficacy. Modifications such as 2′,4′–BNA/LNA with 9–(aminoethoxy)phenoxazine (BNAP–AEO) and 5′–cyclopropyrene (5′–CP) have demonstrated significant reductions in acute and late–onset neurotoxicity, respectively, in both in vitro and in vivo models.
These findings suggest that neurotoxicity of CNS–targeted nucleic acid therapeutics is not an unavoidable adverse effect but a controllable drug–design parameter. A deeper understanding of structure–toxicity relationships and mechanism–based chemical modifications will be essential for expanding the therapeutic potential of nucleic acid drugs in neurological diseases.
