Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease
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 ga...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/67097 |
| _version_ | 1811201519542861824 |
|---|---|
| author | Surender Rajasekaran Caleb P Bupp Mara Leimanis-Laurens Ankit Shukla Christopher Russell Joseph Junewick Emily Gleason Elizabeth A VanSickle Yvonne Edgerly Bryan M Wittmann Jeremy W Prokop André S Bachmann |
| author_facet | Surender Rajasekaran Caleb P Bupp Mara Leimanis-Laurens Ankit Shukla Christopher Russell Joseph Junewick Emily Gleason Elizabeth A VanSickle Yvonne Edgerly Bryan M Wittmann Jeremy W Prokop André S Bachmann |
| author_sort | Surender Rajasekaran |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:21:52Z |
| format | Article |
| id | doaj.art-1498a58c840f461ba483dbb1a62257c5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:21:52Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1498a58c840f461ba483dbb1a62257c52022-12-22T03:52:05ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.67097Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant diseaseSurender Rajasekaran0https://orcid.org/0000-0002-4430-006XCaleb P Bupp1Mara Leimanis-Laurens2Ankit Shukla3Christopher Russell4Joseph Junewick5Emily Gleason6Elizabeth A VanSickle7https://orcid.org/0000-0001-5504-9248Yvonne Edgerly8Bryan M Wittmann9Jeremy W Prokop10André S Bachmann11Pediatric 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 StatesDepartment 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 StatesPediatric 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 StatesDepartment of Pharmacy, Helen DeVos Children’s Hospital, Grand Rapids, United StatesSpectrum Health Office of Research and Education, Grand Rapids, United StatesDepartment of Diagnostic Radiology, Spectrum Health and Helen DeVos Children's Hospital, Grand Rapids, United StatesSpectrum Health Office of Research and Education, Grand Rapids, United StatesMedical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, United StatesSpectrum Health Office of Research and Education, Grand Rapids, United StatesMetabolon, Morrisville, United StatesDepartment 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 StatesDepartment of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United StatesBackground: 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.https://elifesciences.org/articles/67097whole exome sequencingrepurposing drugsglobal metabolomics |
| spellingShingle | Surender Rajasekaran Caleb P Bupp Mara Leimanis-Laurens Ankit Shukla Christopher Russell Joseph Junewick Emily Gleason Elizabeth A VanSickle Yvonne Edgerly Bryan M Wittmann Jeremy W Prokop André S Bachmann Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease eLife whole exome sequencing repurposing drugs global metabolomics |
| title | Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease |
| title_full | Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease |
| title_fullStr | Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease |
| title_full_unstemmed | Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease |
| title_short | Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease |
| title_sort | repurposing eflornithine to treat a patient with a rare odc1 gain of function variant disease |
| topic | whole exome sequencing repurposing drugs global metabolomics |
| url | https://elifesciences.org/articles/67097 |
| work_keys_str_mv | AT surenderrajasekaran repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT calebpbupp repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT maraleimanislaurens repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT ankitshukla repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT christopherrussell repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT josephjunewick repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT emilygleason repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT elizabethavansickle repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT yvonneedgerly repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT bryanmwittmann repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT jeremywprokop repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease AT andresbachmann repurposingeflornithinetotreatapatientwitharareodc1gainoffunctionvariantdisease |