Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.
Jinkuk KimChunguang HuChristelle Moufawad El AchkarLauren E BlackJulie DouvilleAustin LarsonMary K PendergastSara F GoldkindEunjung A LeeAshley KuniholmAubrie SoucyJai VazeNandkishore R BelurKristina FredriksenIva StojkovskaAlla TsytsykovaMyriam ArmantRenata L DiDonatoJaejoon ChoiLaura CornelissenLuis M PereiraErika F AugustineCasie A GenettiKira DiesBrenda BartonLucinda WilliamsBenjamin D GoodlettBobbie L RileyAmy PasternakEmily R BerryKelly A PflockStephen ChuChantal ReedKimberly TyndallPankaj B AgrawalAlan H BeggsP Ellen GrantDavid K UrionRichard O SnyderSusan E WaisbrenAnnapurna PoduriPeter J ParkAl PattersonAlessandra BiffiJoseph R MazzulliOlaf BodamerCharles B BerdeTimothy W YuPublished in: The New England journal of medicine (2019)
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.).