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N Engl J Med. 2019 Oct 24;381(17):1644-1652. doi: 10.1056/NEJMoa1813279. Epub 2019 Oct 9.

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

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From the Divisions of Genetics and Genomics (J.K., C.H., E.A.L., A.S., J.V., R.L.D., J.C., P.B.A., A.H.B., S.E.W., O.B., T.W.Y.), Newborn Medicine (P.B.A., P.E.G.), and Neuroradiology (P.E.G.), the Departments of Neurology (C.M.E.A., D.K.U., A. Poduri), Anesthesiology, Critical Care and Pain Medicine (L.C., C.B.B.), Physical and Occupational Therapy (A. Pasternak, E.R.B., K.A.P.), and Pharmacy (S.C., A. Patterson), the Institutional Centers for Clinical and Translational Research (A.K., B.B., L.W.), and the Manton Center for Orphan Disease Research (C.A.G., P.B.A., A.H.B.), Boston Children's Hospital (A.K., A.T., M.A., L.M.P., K.D., B.B., L.W., B.D.G., B.L.R., A.B.), the Department of Biomedical Informatics (J.K., P.J.P.), Harvard Medical School (J.K., C.M.E.A., E.A.L., L.C., B.D.G., B.L.R., P.B.A., A.H.B., P.E.G., D.K.U., S.E.W., P.J.P., A. Patterson, A.B., O.B., C.B.B., T.W.Y.), and the Gene Therapy Program (A.B.), Boston Children's and Dana-Farber Cancer and Blood Disorders Center (A.K., B.B., L.W.), Boston, Charles River Laboratories, Wilmington (L.E.B.), and Broad Institute of MIT and Harvard (E.A.L., O.B., T.W.Y.), Cambridge - all in Massachusetts; Charles River Laboratories, Montreal (J.D.); University of Colorado School of Medicine, Aurora (A.L.); Pendergast Consulting, Washington, DC (M.K.P.); Goldkind Consulting, Potomac, MD (S.F.G.); the Department of Neurology Feinberg School of Medicine, Northwestern University, Chicago (N.R.B., K.F., I.S., J.R.M.); the Department of Neurology, University of Rochester Medical Center, Rochester, NY (E.F.A.); Brain Hz Consulting, Del Mar, CA (C.R.); Tyndall Consulting, Wake Forest, NC (K.T.); and Brammer Bio, Alachua, FL (R.O.S.).


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.).

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