Niemann-Pick C (NPC) disease is a fatal neurodegenerative storage disorder involving accumulation of unesterified cholesterol (UC) and glycosphingolipids (GSLs) in the lysosomal system. NPC disease animal model studies by us and others have shown the cyclodextrin (CD), 2-hydroxypropyl-β-CD (HPβCD), to significantly: reduce neuronal UC and GSL accumulation; ameliorate behavioral deficits; delay cerebellar Purkinje neuron (PN) loss; and increase life span. Ongoing clinical trials are encouraging but efficacy limited by lower HPβCD dosages required to avoid hearing loss noted in animal studies. Our current work aims to identify safer, efficacious alternatives and the mechanisms of CD therapeutic action. In long-term studies with disease mice, subQ injections of sulfobutylether-β-CD (SBEβCD) and sulfobutylether-γ-CD (SBEγCD) produced little to no hearing loss after 9 weeks, yet still delayed motor deficits and extended life span. SBEγCD was more effective than SBEβCD but less than HPβCD. HPβCD has been thought to exert its effect within the lysosome, directly interacting with stored UC to promote its egress, a process normally carried out by NPC proteins deficient in the disease. However prior collaborative [Dr. L. Szente (Cyclolab, Hungary)] short-term studies comparing 9 CDs, showed no correlation between relative effectiveness in reducing neuronal UC storage in vivo and relative aqueous solubilization of UC. Using disease neuronal cultures, relative UC reduction by different CDs was similar to that in vivo suggesting the disparity between efficacy and solubilization is not due to differential CD penetration of brain. Results of additional culture modeling studies argue against indirect depletion of neuronal UC storage. We also treated mice with HPβCD and miglustat, a GSL synthesis inhibitor previously shown to rescue PNs. HPβCD was more efficacious than miglustat, and combination therapy showed minor improvement over HPβCD alone, primarily for cerebellum. Genome-wide expression studies on mouse neocortex found 34 of 77 gene expression levels altered by disease were returned to wild type levels by HPβCD. Combination therapy did not correct additional genes. Altered expression was identified for several genes not previously implicated in NPC disease, including Ttyh2, Sez6l2, Gpr37 and Plexin B3. Similar ongoing studies on microdissected PNs to identify changes in common for miglustat and HPβCD could help pinpoint critical genes underlying rescue of PNs.

Cyclodextrins in the therapy of Niemann-Pick C disease

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.