Novartis Phase 3 cancer drug Panobinostat may correct Niemann Pick Type C cholesterol defect through inhibiting histone deacetylase (HDAC)

I almost fell off my chair a few minutes ago. I just posted a blog on news from Notre Dame and Cornell about HDAC inhibitors correcting the Niemann Pick Type C defect in cell culture.

I just read on PNAS that the Novartis cancer drug Panobinostat (LBH-589), a Phase 3 drug developed for the treatment of cancer, may be able to halt the progression of Niemann Pick Type C disease, a fatal genetic cholesterol metabolism disorder that affects my twins. Panobinostat inhibits one or more of the histone deacetylase (HDAC) enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.

Here is the abstract — I don’t have the full paper.

Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts

• Niemann-Pick type C (NPC) disease is predominantly caused by mutations in the NPC1 protein that affect intracellular cholesterol trafficking and cause accumulation of unesterified cholesterol and other lipids in lysosomal storage organelles. We report the use of a series of small molecule histone deacetylase (HDAC) inhibitors in tissue culture models of NPC human fibroblasts. Some HDAC inhibitors lead to a dramatic correction in the NPC phenotype in cells with either one or two copies of the NPC1I1061T mutation, and for several of the inhibitors, correction is associated with increased expression of NPC1 protein. Increased NPC1I1061T protein levels may partially account for the correction of the phenotype, because this mutant can promote cholesterol efflux if it is delivered to late endosomes and lysosomes. The HDAC inhibitor treatment is ineffective in an NPC2 mutant human fibroblast line. Analysis of the isoform selectivity of the compounds used implicates HDAC1 and/or HDAC2 as likely targets for the observed correction, although other HDACs may also play a role. LBH589 (panobinostat) is an orally available HDAC inhibitor that crosses the blood–brain barrier and is currently in phase III clinical trials for several types of cancer. It restores cholesterol homeostasis in cultured NPC1 mutant fibroblasts to almost normal levels within 72 h when used at 40 nM. The findings that HDAC inhibitors can correct cholesterol storage defects in human NPC1 mutant cells provide the potential basis for treatment options for NPC disease.

Interestingly, Gleevec, another cancer drug developed by Novartis also works in the NPC mouse model (modestly) and was reported by Paul Greengard to have an effect in the Alzheimer’s model.

Wow. Panobinostat may also work in other neurodegenerative diseases as well such as Alzheimer’s, Huntington’s, ALS, SMA……many others where HDAC inhibition is showing some success!