SUMMARY OF INVENTION
Aerobic glycolysis, a process by which glucose is converted to lactate in the presence of oxygen, is a metabolic hallmark of activated T-cells. However, the specific contribution of aerobic glycolysis to T-cell responses has not been well defined. Investigators at MSK have identified a novel mechanism whereby aerobic glycolysis promotes effector T-cell differentiation.
MSK’s investigators have found that lactate dehydrogenase A (LDHA), the enzyme that catalyzes pyruvate conversion to lactate in aerobic glycolysis, is specifically induced in T-cells and required for effector T-cell differentiation. Treatment with small molecule inhibitors of either LDHA or a downstream enzyme called ATP-citrate lyase (ACL) has been shown to correct inflammatory phenotypes in mice. In addition to targeting LDHA and other downstream enzymes in the aerobic glycolysis process, other therapeutic strategies to inhibit aerobic glycolysis could prove effective for treating inflammatory disorders.
Compelling in vivo results, demonstrating that treatment with an ACL inhibitor is completely protective in a mouse model of multiple sclerosis
Treatment with inhibitors of aerobic glycolysis could be used to treat other T-cell mediated diseases including autoimmune disorders (such as graft-versus-host disease and inflammatory bowel disease) and organ rejection
There is a high unmet need for effective therapies to reduce or prevent severe inflammatory diseases such as multiple sclerosis. Disease-modifying therapies, which delay the course of multiple sclerosis, are currently the only available therapeutic options for multiple sclerosis. There are approximately 400,000 people in the United States and 2.5 million people worldwide living with multiple sclerosis.
PCT application PCT/US2017/051724 filed in September, 2017
Ming Li, PhD, Laboratory Head, Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering
Eileen Flowers, PhD