CFR Researchers Identify Drug that Raises Progranulin Levels

Graduate student Dr. Basar Cenik, in the laboratories of CFR Investigators Drs. Joachim Herz and Gang Yu at the University of Texas, Southwestern Medical Center, is lead author on a recent study entitled, “SAHA (Vorinostat) Upregulates Progranulin Transcription: A Rational Therapeutic Approach to Frontotemporal Dementia.” CFR Investigators Drs. Giovanni Coppola, Bob Farese, Fen-Biao Gao, Dan Geschwind and Bruce Miller are co-authors on the study. Their work, published in the Journal of Biological Chemistry, describes the identification of the drug SAHA (suberoylanilide hydroxamic acid) as a potent inducer of progranulin expression.

Mutations in the gene for progranulin, which reduce the total amount of progranulin protein in the body by more than 50%, are a frequent cause of frontotemporal dementia. Why reduced progranulin levels cause frontotemporal dementia is a major research focus in the CFR. Interestingly, researchers suspect that restoring progranulin to normal levels in mutation carriers may ameliorate the disease, thus making interventions that raise progranulin levels highly promising.

Dr. Cenik and team screened an FDA-approved compound library for small molecules that increased expression of progranulin. Dr. Cenik noted, “FDA-approved compounds are advantageous because they may offer a fast track towards a cure for frontotemporal dementia. Essential features such as toxicity and bioavailability are already known so we don’t have to reinvent the wheel.” They discovered that the drug SAHA, already approved to treat a specific cancer, raised progranulin production to near normal levels not only in mouse cell lines but, importantly, also in cells isolated directly from frontotemporal dementia patients carrying mutations in progranulin.

SAHA inhibits class I and II histone deacetylases (called HDACs), molecules that regulate a specific modification called acetylation made to proteins after they are produced. Dr. Cenik speculates, “Inhibiting acetylation may raise progranulin levels by either acting directly on the progranulin gene or through secondary effects. Our future experiments will help clarify this.” While SAHA does not penetrate the blood brain barrier well, and thus is not an ideal candidate for treating FTD, these results raise the exciting possibility that other HDAC inhibtors with good blood brain barrier penetrance may be viable therapeutic candidates.  

Dr. Cenik and colleagues plan to expand these studies to animal models of progranulin-deficient neurodegeneration. Demonstrating efficacy of HDAC inhibitors in rodents will be a key next step in our efforts to find a treatment for frontotemporal dementia.