Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease

eLife

Joseph Junewick¹  André S Bachmann²  Jeremy W Prokop³  Caleb P Bupp⁴  Ankit Shukla⁵  Elizabeth A VanSickle⁶  Bryan M Wittmann⁷  Mara Leimanis-Laurens⁸  Surender Rajasekaran⁹  Emily Gleason^1,10  Christopher Russell^1,10  Yvonne Edgerly^1,10 

[1] Department of Diagnostic Radiology, Spectrum Health and Helen DeVos Children's Hospital, Grand Rapids, United States;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States;Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, United States;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States;Medical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, United States;Department of Pharmacy, Helen DeVos Children’s Hospital, Grand Rapids, United States;Medical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, United States;Metabolon, Morrisville, United States;Pediatric Critical Care Medicine, Helen DeVos Children’s Hospital, Grand Rapids, United States;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States;Pediatric Critical Care Medicine, Helen DeVos Children’s Hospital, Grand Rapids, United States;Spectrum Health Office of Research and Education, Grand Rapids, United States;Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States;Spectrum Health Office of Research and Education, Grand Rapids, United States;

关键词: whole exome sequencing;    repurposing drugs;    global metabolomics;    Human;   

DOI  :  10.7554/eLife.67097

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Background:Polyamine levels are intricately controlled by biosynthetic, catabolic enzymes and antizymes. The complexity suggests that minute alterations in levels lead to profound abnormalities. We described the therapeutic course for a rare syndrome diagnosed by whole exome sequencing caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC), characterized by neurological deficits and alopecia.Methods:N-acetylputrescine levels with other metabolites were measured using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores established against a reference cohort of 866 children.Results:From previous studies and metabolic profiles, eflornithine was identified as potentially beneficial with therapy initiated on FDA approval. Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support.Conclusions:This work highlights the strategy of repurposing drugs to treat a rare disease.Funding:No external funding was received for this work.

【 授权许可】

CC BY