Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation.

Frontotemporal dementia (FTD) is one of the most important neurodegenerative conditions and Granulin (GRN) is one of the major genes associated to the disease. FTD-GRN patients are still orphan for any evidence-based target-therapy approach. Interestingly, it has been recently found that alkalizing agents rescued haploinsufficiency in cellular models expressing FTD-GRN mutations. We set up a pilot phase II clinical trial in five FTD patients with GRN Thr272s(g.1977_1980delCACT) mutation, to determine if amiodarone (200 mg/day) may (1) reverse progranulin deficiency and (2) delay disease progression. Each patient was scheduled for 7 study visits over 12 months period. We assessed GRN levels at baseline and after amiodarone administration during the treatment course. Somatic and neurologic examinations, along with cognitive and behavioral assessment were recorded as well. No significant effect on peripheral GRN levels was observed. In treated FTD, disease course did not differ when compared with a group of untreated FTD-GRN patients. This is the first trial targeting progranulin rescue in FTD-GRN patients using amiodarone. Despite the negative findings, it may be interesting to extend this attempt to a larger sample of subjects and to other alkalizing agents to restore granulin haploinsufficiency.