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Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.

BACKGROUNDHuntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin.METHODSWe conducted a randomized, double-blind, multiple-ascending-dose, phase 1–2a trial involving adults with early Huntington’s disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF.RESULTSOf the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and −20%, −25%, −28%, −42%, and −38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).CONCLUSIONSIntrathecal administration of HTTRx to patients with early Huntington’s disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT02519036. opens in new tab.)

Spinal muscular atrophy (SMA) is a monogenetic motoneuron disease with onset in childhood or adolescence, clinically characterised by spinal and bulbar muscle weakness and atrophy. SMA type 1 is the acute and thus most severe form of disease, where an early and progressive loss of motoneurons occurs. Recently, the antisense-oligonucleotide nusinersen has been approved for treatment. Nusinersen has to be administered intrathecally by lumbar puncture on days 0, 14, 28 and 63 followed by maintenance therapy at intervals of 4 months. Clinical studies showed an improvement in motor function, particularly in patients with SMA type 1.1 Neurofilaments (Nf) are important structural elements of neurons and their axons.2 In various neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), increased cerebrospinal fluid (CSF) levels of Nf were observed and their usefulness for diagnosis and prognosis was demonstrated.3 Increased CSF tau levels have been found in several neurological diseases associated with significant neuronal loss; however, it still remains a matter of debate whether CSF tau can serve as diagnostic marker in ALS.4 5 Therefore, the question arises, what role CSF Nf and tau play in SMA and how important the use of these parameters in SMA could be with regard to new therapies. …