期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 381, 期 17, 页码 1644-1652出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1813279
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资金
- Mila's Miracle Foundation
- Boston Children's Hospital
- Harvard Catalyst Clinical and Translational Research Center (National Center for Advancing Translational Sciences) [8UL1TR000170]
- Mooney Family Fund
- Boston Children's Hospital Translational Research Program
- Manton Center for Orphan Disease Research
- Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (IDDRC) Molecular Genetics Core Laboratory
- National Institutes of Health [1U54HD090255]
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.) A child with a neuronal ceroid lipofuscinosis was found to carry loss-of-function mutations in the gene MFSD8 (CLN7). A year after genetic diagnosis, the child began treatment with an oligonucleotide drug that was designed to correct the aberrant pre-messenger RNA splicing caused by one of these mutations.
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