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Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

Jinkuk Kim, Ph.D., Chunguang Hu, M.D., Ph.D., Christelle Moufawad El Achkar, M.D., Lauren E. Black, Ph.D., Julie Douville, Ph.D., Austin Larson, M.D., Mary K. Pendergast, J.D., Sara F. Goldkind, M.D., Eunjung A. Lee, Ph.D., Ashley Kuniholm, B.S., Aubrie Soucy, B.A., Jai Vaze, B.A., Nandkishore R. Belur, M.S., Kristina Fredriksen, B.S., Iva Stojkovska, B.S., Alla Tsytsykova, Ph.D., Myriam Armant, Ph.D., Renata L. DiDonato, B.S., Jaejoon Choi, Ph.D., Laura Cornelissen, Ph.D., Luis M. Pereira, Ph.D., Erika F. Augustine, M.D., Casie A. Genetti, M.S., Kira Dies, Sc.M., Brenda Barton, R.N., Lucinda Williams, D.N.P., Benjamin D. Goodlett, Ph.D., Bobbie L. Riley, M.D., Amy Pasternak, D.P.T., P.C.S., Emily R. Berry, D.P.T., Kelly A. Pflock, D.P.T., P.C.S., Stephen Chu, Pharm.D., Chantal Reed, Ph.D., Kimberly Tyndall, B.A., Pankaj B. Agrawal, M.B., B.S., M.M.Sc., Alan H. Beggs, Ph.D., P. Ellen Grant, M.D., David K. Urion, M.D., Richard O. Snyder, Ph.D., Susan E. Waisbren, Ph.D., Annapurna Poduri, M.D., M.P.H., Peter J. Park, Ph.D., Al Patterson, Pharm.D., Alessandra Biffi, M.D., Joseph R. Mazzulli, Ph.D., Olaf Bodamer, M.D., Ph.D., Charles B. Berde, M.D., Ph.D., and Timothy W. Yu, M.D., Ph.D. (NEJM)

October 24, 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.)



N Engl J Med 2019; 381:1644-1652


DOI: 10.1056/NEJMoa1813279


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