Margot A Cousin, Aditi I Dagli, Laurence Mignon, Jaimin S Shah, Mercedes Prudencio, Tania F Gendron, Angita Jain, Evan Udine, Marka van Blitterswijk, Erik H Middlebrooks, Megan H Donahue, Jany E Dagher, Jens O Watzlawik, Wolfdieter Springer, Tejal Parekh, Zachary T McEachin, Leonard Petrucelli, Björn Oskarsson
Individualized 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.
BACKGROUND: Pathogenic 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.
METHODS: In 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.
FINDINGS: No 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.
CONCLUSIONS: Individualized 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.
FUNDING: This study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.