Patient-customized oligonucleotide therapy for a rare genetic disease

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

528 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1644-1652
Number of pages9
JournalNew England Journal of Medicine
Volume381
Issue number17
DOIs
StatePublished - Oct 24 2019

Funding

Supported by Mila’s Miracle Foundation, Boston Children’s Hospital, the Harvard Catalyst Clinical and Translational Research Center (through National Center for Advancing Translational Sciences grant 8UL1TR000170), the Mooney Family Fund, and the Boston Children’s Hospital Translational Research Program. Claritas Genomics and WuXi NextCODE provided whole-genome sequencing and Clinical Laboratory Improvement Amendments confirmation. The process of obtaining consent, the enrollment of patients, and molecular genetic analyses were conducted with the assistance and support of the Manton Center for Orphan Disease Research and the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (IDDRC) Molecular Genetics Core Laboratory, which is supported in part by a grant from the National Institutes of Health (1U54HD090255).

ASJC Scopus subject areas

  • General Medicine

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