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.

KIF1A 相关神经疾病 （KAND） 是一种神经退行性且通常致命的超罕见疾病，具有广泛的表型谱，与 KIF1A 中的大部分杂合子从头错义变异相关。反义寡核苷酸治疗代表了一种很有前途的超罕见疾病个性化治疗方法。在这里，我们报告了一名患有严重 KAND 的患者的病例，其特征是顽固性行为停滞并携带 KIF1A 中的 p.Pro305Leu 变体，该患者接受了鞘内注射等位基因特异性反义寡核苷酸治疗，专门设计用于从致病性等位基因中降解 mRNA。第一次鞘内给药因硬膜外脑脊液收集而复杂化，并自行消退。否则，反义寡核苷酸在 9 个月的治疗中是安全的，耐受性良好。大多数结局指标，包括行为停止发作的严重程度、跌倒次数和生活质量，都有所改善。6 分钟步行测试距离变化不大，但观察到步态的质变导致跌倒的显着减少和独立性提高。认知表现稳定，不会随着时间的推移而退化。我们的研究结果为等位基因特异性反义寡核苷酸作为 KAND 的可能治疗方法的安全性和有效性提供了初步见解。