Therapeutic potential of histone deacetylase inhibitor for treatment of Niemann-Pick type C1 disease

摘要

BackgroundNiemann-Pick type C (NPC) is a rare, autosomal recessiveneurodegenerative lysosomal storage disorder (LSD)caused due to mutation in either npc1 or npc2 genes.However, 95% of the reported cases are caused due tomutation in npc1 gene and only 5% due to the mutation innpc2 gene. Mutations in either of these two genes resultsin similar phenotype such that there is an abnormal accumulationof unesterified cholesterol and glycosphingolipidsin late endosomes/ lysosomes (LE/Ly) of many cell types.NPC1 is a multi-spanning transmembrane protein localizedin limiting membrane of LE/Ly whereas NPC2 issoluble cholesterol binding protein localized in the lumenof LE/Ly. There are no therapeutic options to treat thedisease and the children born with this defect die beforethe age of 20 years. Miglustat, a drug used to treatGaucher disease has been reported to stabilize NPCpatients and has also been approved for treating NPCpatients in Europe. Infusion of very high dose of chemicalchaperone like 2-hydroxypropyl-b-cyclodextrin (HPBCD)several times a week has also been shown to reduce thecholesterol load in peripheral tissues. Unfortunately, theblood brain barrier (BBB) cross over capability of HPCD isvery poor and hence requires intrathecal CNS injections.ResultsWe have found that the treatment of several histonedeacetylase inhibitors (HDACi), corrects the NPC defectspecifically in human patient derived NPC1, but not inNPC2 fibroblast. Amongst the HDACi tested Vorinostatis a FDA approved drug that has been shown to cross BBBand is currently used in clinic for treatment of cutaneousT-cell lymphoma and many other type of cancer. Ourinitial study was conducted on most common mutation“I1061T” found in human patients but since then we havetested the effect of Vorinostat and other HDACi’s onseveral different patient derived mutant fibroblasts.ConclusionsOur data indicate that Vorinostat is effective in rescuingthe phenotype in most cases but to a varying degree.This is a promising breakthrough example of repurposingexisting FDA approved drug for the treatment of NPC1and other LSDs.