Sharon J. Sha1, Zachary A. Miller1, Sang-won Min2, Yungui Zhou2, Jesse Brown1, Laura L. Mitic1,3, Anna Karydas1, Mary Koestler1, Richard Tsai1, Chiara Corbetta-Rastelli1, Sophie Lin1, Emma Hare1, Scott Fields4, Kirsten E. Fleischmann5, Ryan Powers1, Ryan Fitch1, Lauren Herl Martens6, Mehrdad Shamloo7, Anne M. Fagan8, Robert V. Farese6
1Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA
2Gladstone Institute of Neurodegenerative Disease, San Francisco, CA
3Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA
4Investigational Drug Service, UCSF Medical Center, San Francisco, CA
5Division of Cardiology, University of California, School of Medicine, San Francisco, CA
6Gladstone Institute of Cardiovascular Disease, San Francisco, CA
7Institute for Neuro-Innovation and Translational Neurosciences, Stanford, CA
8Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
Tóm tắt
AbstractIntroductionFrontotemporal 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.MethodsWe 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.ResultsThere 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.DiscussionWhile well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.
