Small Molecules Suppressors of APOE Gene Expression and Cerebral Vascular Amyloid Pathology

Technology

Previous research has demonstrated that APOE4 is strongly associated with increased amyloid accumulation observed in CAA and AD. The researchers have shown that this amyloid accumulation in APOE4 pericytes is due to increased APOE protein levels resulting from dysregulated calcineurin (CaN)/NFAT signaling. CaN/NFAT inhibitors (FK506 and cyclosporine A) significantly reduced APOE expression and vascular amyloid pathology, even at sub-immunosuppressive levels. Building on these findings, the non-immunosuppressant cyclosporins described in this invention were found to be significantly more potent, act with faster kinetics, and reduce APOE expression at lower doses than immunosuppressive cyclosporins such as cyclosporin A.

Problem Addressed

Although cyclosporin A and FK506 can reduce APOE expression in brain cells and prevent or reverse cerebrovascular pathologies associated with AD and CAA, their immunosuppressive activity increases the risk of infection and cancer, creating significant toxicity concerns. This invention circumnavigates these challenges by introducing non-immunosuppressive cyclosporin compounds which are more potent, faster-acting, and effective at lower doses than immunosuppressive cyclosporins such as cyclosporin A, without immune suppression.

Advantages

• Selective inhibition of APOE expression without immunosuppression  
• More potent, faster kinetics, and effective at lower doses than immunosuppressant cyclosporins such as cyclosporin A
• Preservation of blood-brain barrier integrity through inhibition of cyclophilin A-driven vascular damage
• Improved safety compared to immunosuppressive agents, reducing risks of infection and cancer