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

TitleAn 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from gene mutations.
Publication TypeJournal Article
Year of Publication2017
AuthorsSha SJ, Miller ZA, Min S-W, Zhou Y, Brown J, Mitic LL, Karydas A, Koestler M, Tsai R, Corbetta-Rastelli C, Lin S, Hare E, Fields S, Fleischmann KE, Powers R, Fitch R, Martens LHerl, Shamloo M, Fagan AM, Farese RV, Pearlman R, Seeley W, Miller BL, Gan L, Boxer AL
JournalAlzheimers Dement (N Y)
Volume3
Issue4
Pagination507-512
Date Published2017 Nov
ISSN2352-8737
Abstract

Introduction: Frontotemporal lobar degeneration-causing mutations in the progranulin () 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 mutation carriers.

Methods: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight 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.

DOI10.1016/j.trci.2017.08.002
Alternate JournalAlzheimers Dement (N Y)
PubMed ID29124108
PubMed Central IDPMC5671622
Grant ListK23 AG048291 / AG / NIA NIH HHS / United States
R01 AG038791 / AG / NIA NIH HHS / United States
U01 AG045390 / AG / NIA NIH HHS / United States
U54 NS092089 / NS / NINDS NIH HHS / United States