|Title||An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from gene mutations.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Sha 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|
|Journal||Alzheimers Dement (N Y)|
|Date Published||2017 Nov|
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.
|Alternate Journal||Alzheimers Dement (N Y)|
|PubMed Central ID||PMC5671622|
|Grant List||K23 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