Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder

Abstract

KIF1A-associated neurological disorder (KAND) is a neurodegenerative and often lethal ultrarare disease with a wide phenotypic spectrum associated with largely heterozygous de novo missense variants in KIF1A. Antisense oligonucleotide treatments represent a promising approach for personalized treatments in ultrarare diseases. Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele. The first intrathecal administration was complicated by an epidural cerebrospinal fluid collection, which resolved spontaneously. Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved. There was little change in the 6-min Walk Test distance, but qualitative changes in gait resulting in meaningful reductions in falls and increasing independence were observed. Cognitive performance was stable and did not degenerate over time. Our findings provide preliminary insights on the safety and efficacy of an allele-specific antisense oligonucleotide as a possible treatment for KAND.

Extended Data Fig. 1 |. Run-in and post-treatment electroencephalography.

Run-in (a, c) and post-treatment (b, d) electroencephalography (EEG). Awake EEG (a, b) shows diffuse slowing and excess beta frequency activity related to benzodiazepine therapy. A posterior dominant rhythm (PDR) of 9 Hz is appreciated (arrow) in B, recorded after the third dose. Sleep EEG (c, d) shows abundant spikes (arrowheads) in the temporal and parietal regions at the onset of sleep. A modest improvement in spike incidence is shown in D, recorded after the second dose.

Extended Data Fig. 2 |. Cognitive performance over the course of the study.

Cognitive performance over the course of the study as evaluated by the differential ability scales-second edition (DAS-II).

Fig. 1 |. ASO design and potency.

a, The pathogenic c.914C>T p.Pro305Leu variant is in trans with a common benign SNP (rs7578279) at position chr2:240737847A–G (hg38). The ASO binds the mRNA from the allele carrying c.914C>T p.Pro305Leu at positions chr2:240737833–240737853 (hg38), which overlaps with the benign SNP on the WT allele. b, Dose–response of nL-KIF1-001 in vitro. Induced pluripotent stem cell-derived neurons were treated by free uptake with increasing concentrations of ASO for 5 days. RNA was isolated and KIF1A mRNA was evaluated using quantitative PCR with reverse transcription (RT–qPCR) (TaqMan). nL-KIF-001 showed an IC50 of 7.4 μM and high selectivity for the mRNA from the pathogenic allele over WT KIF1A. Each data point was derived from six independent biological replicates where KIF1A expression was normalized to cyclophilin and compared to untreated control. Data from these replicates are expressed as the mean value ± s.d.

Fig. 2 |. Clinical outcomes from 50 days before the first dose to day 360.

The dates of dosing are represented by the dashed red lines. a, Number of spells of behavioral arrest as reported by the parents. b, Duration of the longest spells of behavioral arrest as reported by the parents. c, SWI as determined using overnight EEG. d, Number of falls per day as reported by the parents. e, Distance walked during the 6-min Walk Test. f, QoL determined using the Quality of Life Inventory-Disability (QI-Disability) scale. Blanks correspond to the absence of data. Because of their high frequency, the parents were unable to accurately count the number of seizures on days 18, 198 and 203.