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.
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Data availability
To protect the privacy of the patient, the phenotypic data generated during the current study are available upon request from the corresponding author (wendy.chung@childrens.harvard.edu) within a month on request and completion of a data transfer agreement. Source data are provided with this paper.
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Acknowledgements
Funding from the study was provided by NINDSR01NS114636 and UL1TR001873. The funders were not involved in study design or data collection, management, analysis or interpretation. We thank the patient and her family for their participation and partnership. We thank J. Cho, A. Gregory, T. Cole, A. Watt, J. Ochaba and F. Bennett for their expertise and advice. We also thank the Division of Regulatory Operations for Neuroscience at the US FDA for their guidance.
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A.Z., J.C., J.M.B., T.T.S., R.J.F., D.U., C.H.K., J.M. and W.K.C. contributed to the clinical management of the patient. S.G., J.D., L.M., J.G.G. and S.T.C. created the ASO. All authors were involved in the writing of the paper.
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W.K.C. is on the Board of Directors at Prime Medicine and Rallybio. The other authors declare no competing interests.
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Nature Medicine thanks Annemieke Aartsma-Rus and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Anna Maria Ranzoni, in collaboration with the Nature Medicine team.
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Extended data
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).
Supplementary information
Supplementary Information
Supplementary Table 1.
Supplementary Video 1
Run-in and post-treatment video of the patient.
Source data
Source data for Figs. 1 and 2
Statistical source data. Sheet summary for Fig. 1, (Q1, Q2 and Q3). Sheet summary for Fig. 2.
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Ziegler, A., Carroll, J., Bain, J.M. et al. Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder. Nat Med (2024). https://doi.org/10.1038/s41591-024-03197-y
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DOI: https://doi.org/10.1038/s41591-024-03197-y
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