Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis. (PubMed, Methods Mol Biol) - Oct 1, 2026 - "Although pivotal trials did not meet primary functional endpoints (ALSFRS-R) at 28 weeks, longer-term and real-world observations suggest potential clinical benefit with earlier initiation, a hypothesis now being tested in presymptomatic SOD1 variant carriers. This chapter reviews the development of gapmer ASOs for ALS with a focus on tofersen-covering chemistry and mechanism, preclinical validation, clinical efficacy and safety, biomarker readouts, and ongoing trials-while outlining key challenges (CNS delivery, adverse event monitoring, endpoint sensitivity) and future directions, including earlier intervention guided by biomarkers and extension to additional genetic forms of ALS."
Biomarker • Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • CSF NfL • NEFL • Plasma NfL
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Hidenori Moriyama; Toshifumi Yokota; Yuriko Nakamura
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