Amylin and amylin formed aggregates are distinct: one is a gut-brain hormone via the physiological pathway, the other one is a factor for diabetes via the pathological pathway. Pramlintide is an amylin analog without aggregating character and a diabetes drug approved by the Food and Drug Administration (FDA). Recent studies suggest that pramlintide has the potential to be repositioned for Alzheimer's disease (AD). As a human clinical trial of pramlintide for AD is costly and time-consuming, we propose to use quantitative systems pharmacology (QSP) to characterize the genotypic and phenotypic changes influenced by pramlintide that will be informative for a go/no-go decision on a large phase II/III clinical trial. The central hypothesis for our proposed study is that pramlintide will enhance the physiological amylin-amylin receptor (AmR) pathway via cognate AmR to reduce AD pathology and increase synapsis in the brain, and thus improve cognition. This will be a combined study of computational analysis and translational approach with three specific aims.
Aim 1 will use existing data to conduct a systems biology analysis to characterize the amylin-AmR pathway for AD.
Aim 2 will use cells and AD mouse models to conduct a proof-of-principle study of the effects of pramlintide on the amylin-AmR pathway.
Aim 3 will use human subjects to conduct a proof-of- principle study of the effects of pramlintide on the amylin-AmR pathway. Should our proposed study support the concept that pramlintide to be repositioned for AD, it will lay foundation for a clinical trial on the drug for AD.
Pramlintide is an amylin analog and an FDA approved diabetic drug with a favorable safety profile and has the potential to be repurposed for Alzheimer's disease (AD). The significance of the proposed study is to use quantitative systems pharmacology (QSP) and translational study to characterize the genotypic and phenotypic changes influenced by pramlintide. Since clinical trials for AD are costly and time-consuming, this study will be informative for a go/no- go decision on a large phase II/III clinical trial of pramlintide for the disease.
