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An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations. Alzheimer's & dementia (New York, N. Y.) Sha, S. J., Miller, Z. A., Min, S., Zhou, Y., Brown, J., Mitic, L. L., Karydas, A., Koestler, M., Tsai, R., Corbetta-Rastelli, C., Lin, S., Hare, E., Fields, S., Fleischmann, K. E., Powers, R., Fitch, R., Martens, L. H., Shamloo, M., Fagan, A. M., Farese, R. V., Pearlman, R., Seeley, W., Miller, B. L., Gan, L., Boxer, A. L. 2017; 3 (4): 507–12

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.

View details for DOI 10.1016/j.trci.2017.08.002

View details for PubMedID 29124108