This technology relates to the identification and use of a group of compounds that activate the AMP-activated protein kinase (AMPK) and also effectively reduce lysosomal cholesterol accumulation in patients with Niemann-Pick disease Type C (NPC). Clinical trials are currently underway to determine the efficacy of beta-cyclodextrin in treating patients with NPC. A potential mechanism has been proposed indicating that beta-cyclodextrin activated AMP-activated protein kinase, leading to restoration of autophagy in cells from NPC patients. A computer modeling was used to identify the group of compounds that bind and activate AMPK. Eight of the compounds were found to effectively reduce cholesterol accumulation in lysosomes of cells from NPC patients.
The small molecule AMPK modulators can be optimized for better penetration of the blood-brain barrier. This is advantageous over beta-cyclodextrin, which is impermeable to the blood-brain barrier and needs to be directly injected into the central nervous system. In addition, the allosteric modulation of AMPK function by these compounds is more tolerable as a treatment because beta-cyclodextrin directly activates the AMPK alpha-subunit which can cause significant cytotoxicity.