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

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.

SUBMITTER: Sha SJ

PROVIDER: S-EPMC5671622 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Sha Sharon J SJ Miller Zachary A ZA Min Sang-Won SW Zhou Yungui Y Brown Jesse J Mitic Laura L LL Karydas Anna A Koestler Mary M Tsai Richard R Corbetta-Rastelli Chiara C Lin Sophie S Hare Emma E Fields Scott S Fleischmann Kirsten E KE Powers Ryan R Fitch Ryan R Martens Lauren Herl LH Shamloo Mehrdad M Fagan Anne M AM Farese Robert V RV Pearlman Rodney R Seeley William W Miller Bruce L BL Gan Li L Boxer Adam L AL

Alzheimer's & dementia (New York, N. Y.) 20170912 4

<h4>Introduction</h4>Frontotemporal lobar degeneration-causing mutations in the progranulin (<i>GRN</i>) 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 <i>GRN</i> mutation carriers.<h4>Methods</ ...[more]

PMID: 29124108

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Dataset Information

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

Publications

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

Similar Datasets

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