Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

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


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.).

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Child
  • Child Development
  • Drug Discovery
  • Drugs, Investigational / therapeutic use
  • Electroencephalography
  • Female
  • Humans
  • Membrane Transport Proteins / genetics*
  • Mutagenesis, Insertional*
  • Neuronal Ceroid-Lipofuscinoses / drug therapy*
  • Neuronal Ceroid-Lipofuscinoses / genetics*
  • Neuropsychological Tests
  • Oligonucleotides, Antisense / therapeutic use*
  • Precision Medicine*
  • RNA, Messenger
  • Rare Diseases / drug therapy*
  • Seizures / diagnosis
  • Seizures / drug therapy
  • Skin / pathology
  • Whole Genome Sequencing


  • Drugs, Investigational
  • MFSD8 protein, human
  • Membrane Transport Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger