Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

TLDR

Genome sequencing is often pivotal in diagnosing rare diseases, yet many of these conditions lack specific treatments. The study aimed to show how molecular diagnosis of a rare, fatal neurodegenerative disorder enabled the design, testing, and manufacture of a patient‑specific splice‑modulating antisense oligonucleotide, milasen. Cell‑based proof‑of‑concept experiments guided the rapid development and initiation of an N‑of‑1 trial of milasen within one year of first contact. No serious adverse events occurred, and treatment was associated with objective seizure reduction by EEG and parental reports, indicating a potential template for rapid patient‑customized therapies. The study was funded by Mila's Miracle Foundation and other supporters.

Abstract

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).