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. 2017 Sep 12;3(4):507-512.
doi: 10.1016/j.trci.2017.08.002. eCollection 2017 Nov.

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

Sharon J Sha  1 , Zachary A Miller  1 , Sang-Won Min  2 , Yungui Zhou  2 , Jesse Brown  1 , Laura L Mitic  1   3 , Anna Karydas  1 , Mary Koestler  1 , Richard Tsai  1 , Chiara Corbetta-Rastelli  1 , Sophie Lin  1 , Emma Hare  1 , Scott Fields  4 , Kirsten E Fleischmann  5 , Ryan Powers  1 , Ryan Fitch  1 , Lauren Herl Martens  6 , Mehrdad Shamloo  7 , Anne M Fagan  8 , Robert V Farese Jr  6 , Rodney Pearlman  3 , William Seeley  1 , Bruce L Miller  1 , Li Gan  2 , Adam L Boxer  1
Affiliations

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

Sharon J Sha et al. Alzheimers Dement (N Y). .

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.

Keywords: Dementia; Frontotemporal dementia; Genetics; Nimodipine; Progranulin.

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Figures

Fig. 1
Fig. 1
Nimodipine had no effect on secondary outcome measures in humans, including plasma and CSF PGRN levels and brain volume loss. (A) The mean change in plasma PGRN between baseline (day 0) and the end of the trial (day 56 ± 7) was −1.47 ± 2.1 ng/mL. (B) The mean change in CSF PGRN between baseline (day 0) and the end of the trial (day 56 ± 7) was −0.09 ± 0.04 ng/mL. (C) Elevated neurofilament light chain correlated with disease severity. (P = .0002, Mann-Whitney) (D) Elevated tau correlated with disease severity (P = .0002, Mann-Whitney). (E) A significant cluster of gray matter loss was detected in the left middle frontal gyrus (yellow = 20% loss) (cluster extent of 1431 voxels, peak MNI coordinate: −51, 28, 28). (F) The change in brain volume loss was driven by symptomatic mutation carriers.
Supplemental Fig. 1
Supplemental Fig. 1
(A and B) Treatment with ionomycin or thapsigargin lowered levels of secreted PGRN in microglial BV2 cells. BV2 cells were treated with indicated concentrations of either ionomycin (A) or thapsigargin (B) for 8 hours. DMSO was used as vehicle control. Ponceau S staining showed similar loading of protein. n = 9–12 in three independent experiments (ionomycin), n = 4–6 in two independent experiments (thapsigargin). ∗∗∗, P < .001, one-way ANOVA with Tukey-Kramer post hoc test. (C) Nimodipine significantly increased hippocampal PGRN levels in Grn+/– mice. Nimotop (NMP) or vehicle (Veh) (PBS with 17% PEG-400) was administered via oral gavage for 2–3 weeks. Hippocampal PGRN levels were measured by ELISA analysis. n = 25–26 mice/treatment, ∗, P < 0.05, unpaired Student t-test. ANOVA, analysis of variance; ELISA, enzyme-linked immunosorbent assay; PGRN, progranulin protein.
Supplemental Fig. 2
Supplemental Fig. 2
CONSORT diagram of subject enrollment.
Supplemental Fig. 3
Supplemental Fig. 3
Nimodipine dosing.
See this image and copyright information in PMC

References

    1. Cruts M., Gijselinck I., van der Zee J., Engelborghs S., Wils H., Pirici D. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442:920–924. - PubMed
    1. Gass J., Cannon A., Mackenzie I.R., Boeve B., Baker M., Adamson J. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006;15:2988–3001. - PubMed
    1. Baker M., Mackenzie I.R., Pickering-Brown S.M., Gass J., Rademakers R., Lindholm C. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916–919. - PubMed
    1. Cenik B., Sephton C.F., Dewey C.M., Xian X., Wei S., Yu K. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem. 2011;286:16101–16108. - PMC - PubMed
    1. Holler C.J., Taylor G., McEachin Z.T., Deng Q., Watkins W.J., Hudson K. Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia. Mol Neurodegener. 2016;11:46. - PMC - PubMed