ArticleMed (New York, N.Y.)2026
N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.
Article in Med (New York, N.Y.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06392126 (An Open-label Study of an Experimental Antisense Oligonucleotide Treatment for a Single Participant With Amyotrophic Lateral Sclerosis), which is not on this map. Not yet cited in PubMed.
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The trial behind it
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An Open-label Study of an Experimental Antisense Oligonucleotide Treatment for a Single Participant With Amyotrophic Lateral Sclerosis (ALS) Due to a Pathogenic Variant in CHCHD10
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Authors and funding
18 authors.
Funding
Abstract
backgroundPathogenic CHCHD10 variants cause a rare, dominantly inherited form of amyotrophic lateral sclerosis (ALS). Non-allele-selective CHCHD10 knockdown may mitigate a toxic gain-of-function mechanism. We evaluated nL-CHCHD-001 in one participant with the p.Arg15Leu variant.
methodsIn this open-label N-of-1 study, 320-gapmer antisense oligonucleotides (ASOs) were screened, and a lead candidate was selected according to specificity and non-clinical safety criteria. Six intrathecal doses were administered over 12 months (three 50-mg doses followed by three 75-mg doses). Prespecified primary outcomes were 12-month changes in functional, cognitive, quality-of-life, respiratory, neurofilament light (NfL), and survival measures; secondary outcomes assessed were safety and tolerability. Analyses were descriptive.
findingsNo serious adverse events occurred. Post-dose headache and fatigue were mild to moderate, and cerebrospinal fluid safety results were unremarkable. Plasma NfL decreased by approximately 50% from a mildly elevated pretreatment baseline and entered the laboratory reference range. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score increased from 33 to 36, vital capacity increased from 48% to 55% (as predicted), cognitive and quality-of-life scores remained stable, and the participant was alive at 12 months.
conclusionsIndividualized CHCHD10-directed treatment was feasible and well tolerated and was temporally associated with biomarker and clinical stability or improvement. This N-of-1 study demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit. These findings support further evaluation of nL-CHCHD-001 and highlight NfL as a practical treatment-response biomarker for personalized therapeutics in ALS. CLINICALTRIALS: gov: NCT06392126.
fundingThis study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.
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