NU 2020-021

INVENTORS
Hossein Ardehali*
Adam De Jesus

SHORT DESCRIPTION 
A drug that elicits inflammatory response as a therapeutic for immunodeficiency disorders

ABSTRACT
The primary hallmarks of Immunodeficiency disorders include suppression of the immune system and impaired response to infection, which can be fatal. There is currently a lack of safe and effective therapies for patients suffering from immunodeficiency disorders as the available therapeutics are associated with detrimental side effects. Northwestern researchers have repurposed Clotrimazole for the treatment of immunodeficiency disorders. Clotrimazole is an antifungal drug that disassociates hexokinase I (HK1) from the outer membrane of mitochondria. Dislocation and translocation of HK1 into the cytoplasm of immune cells inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which alters normal energy metabolism and increases activation of the pentose phosphate pathway (PPP). Stimulation of the PPP facilitates cytokine release and inflammatory activation in response to foreign pathogens. Clotrimazole was effective in restoring normal immune function in immunocompromised patients as well as those susceptible to organ failure.

APPLICATIONS 
•    Immune activation
•    Treatment for HIV and other immunodeficiency diseases
•    Normal restorative function to patients suffering from immune failure

ADVANTAGES 
•    Novel pathway for treatment of immune deficiency broadens field of potential treatments
•    No current therapies activate cytokines, establish possibility for more effective/combined regiment
•    Stimulation of pentose phosphate pathway activates innate immune response

PUBLICATION
De Jesus A, Keyhani-Nejad F, Pusec CM, Goodman L, Geier JA, Stoolman JS, Stanczyk PJ, Nguyen T, Xu K, Suresh KV, Chen Y, Rodriguez AE, Shapiro JS, Chang HC, Chen C, Shah KP, Ben-Sahra I, Layden BT, Chandel NS, Weinberg SE, Ardehali H (2022). Hexokinase 1 cellular localization regulates the metabolic fate of glucose. Molecular Cell, 82(7):1261-1277.e9. 

IP STATUS
US patent and PCT applications have been filed.

Treatment with Clotrimazole (CLT) significantly ablates the colocalization of HK1 with mitochondria, facilitating an immune response.