Positive Clinical Observations from n-Lorem Treated, KIF1A Nano-rare Patient Published in Nature Medicine

In this issue of Nature Medicine (Ziegler, A., 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), our colleagues and we report the response of a patient with a toxic gain of function mutation in KIF1A to a personalized antisense oligonucleotide (ASO) medicine designed for this particular patient. KIF1A is a gene that encodes a protein necessary for movement of cargo-laden membrane enclosed vesicles called Late Endosomes along the microtubule network of the axons of neuronal cells. Axons are long microscopic projections from the bodies of neuronal cells (some are as long as a meter). Since axons transmit signals between neurons and other cells, they are critical to the function of the central nervous system, but their length means that providing the nutrients required and getting rid of waste poses daunting problems for neuronal cells. One can think of microtubules as biological railroads along which late endosome carrying cargo move like cars in a freight train. Mutations in KIF1A disrupt microtubular trafficking and therefore lead to neurodegenerative diseases.

Our patient experienced severe seizures, progressive loss of mobility, progressive loss of language ability and a severe pain syndrome. Prior to treatment, she had progressed to being nearly wheelchair fast and non-verbal. What is truly remarkable is that with ASO treatment, she rapidly experienced reduced seizures and improved in mobility and language while experiencing far less pain. This patient has now been treated for 20 months and continues to demonstrate signs of improvement across many different measures.

Because KIF1A is an essential gene, our patient required an “alle-selective” RNAseH1 ASO designed to reduce only the mutant RNA and protein while sparing the normal RNA and protein. There is no other drug discovery technology capable of that level of selectivity and the response of this KIF1A patient once again demonstrates the power of the technology and the value being created by n-Lorem.

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