An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations

Sharon J. Sha, Zachary A. Miller, Sang won Min, Yungui Zhou, Jesse Brown, Laura L. Mitic, Anna Karydas, Mary Koestler, Richard Tsai, Chiara Corbetta-Rastelli, Sophie Lin, Emma Hare, Scott Fields, Kirsten E. Fleischmann, Ryan Powers, Ryan Fitch, Lauren Herl Martens, Mehrdad Shamloo, Anne M. Fagan, Robert V. FareseRodney Pearlman, William Seeley, Bruce L. Miller, Li Gan, Adam L. Boxer

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Introduction Frontotemporal lobar degeneration–causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration–approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. Methods We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. Results There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of −5.2 ± 10.9% in plasma and −10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. Discussion While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

Original languageEnglish
Pages (from-to)507-512
Number of pages6
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Volume3
Issue number4
DOIs
StatePublished - Nov 2017

Keywords

  • Dementia
  • Frontotemporal dementia
  • Genetics
  • Nimodipine
  • Progranulin

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