IMPDH inhibitor Mizoribine for the treatment of Tuberous Sclerosis and LAM

Results from Brendan Manning’s lab at Harvard’s School of Public Health suggests that there is potential to use Bredinin (mizoribine), a drug widely used as an immunosuppressive drug in Japan and Europe, as an anti-tuberous sclerosis complex (TSC) agent.

TSC is a genetic disorder that results from mutations in either TSC1 or TSC2 genes. The disorder causes tumors to develop in the brain and other organs throughout the body. Patients that are severely affected are characterized by having seizures, developmental delay, intellectual disability, and autism. The prevalence of TSC in the U.S. is approximately 50,000 people. The current standard of care, Rapamycin (or its analogs), is approved to treat TSC, though rapalogs largely induce cytostatic, rather than cytotoxic responses, and tumors rapidly regrow when treatment is stopped. Thus, there is great need for new treatments.

TSC inhibits mTOR, a master regulator of anabolic growth and proliferation that signals from nutrients, energy, and growth factors to control downstream metabolic outputs. Loss of TSC triggers constitutive activation of mTORC1 and subsequent development of the disease TSC. Under favorable growth conditions, mTORC1 stimulates synthesis of major macromolecules required for cell growth and proliferation, including nucleotides. Inosine monophosphate dehydrogenase (IMPDH) is the rate limiting enzyme in guanylate nucleotide synthesis, stimulated by mTORC1.

Research from the Manning lab at Harvard has shown that cells with TSC deficiency have increased dependence on nucleotide synthesis, which can be targeted using the IMPDH inhibitor mizoribine. The lab has further shown that mizoribine has anti-tumor efficacy in both genetic and xenograft tumor models of TSC. These results suggest that widely used clinical IMPDH inhibitors are good candidates for repurposing as anti-tumor agents for tumors with elevated mTORC1 signaling, such as those in TSC patients.

Mizoribine is currently approved for use in Japan and Europe and has a favorable safety and tolerability profile. Finally, given that mizoribine is not approved in the U.S., the 505(b)(2) regulatory pathway presents a favorable regulatory pathway in addition to ~5 year market exclusivity.

Intellectual Property Status: Patent(s) Pending