Potassium Channel Modulation as a Therapeutic Strategy for Chronic Inflammatory Disease

Beeton High Res (320x240)
Dr. Christine Beeton, Department of Molecular Physiology

Potassium channels play crucial roles in regulating the function of a large number of electrically excitable cells and non-excitable cells. Potassium channels are highly diverse in their subunit composition and physiological function, but each type has restricted tissue distribution. Therefore, it is possible to selectively target one channel type to modulate cell activity in a tissue-specific manner, which makes potassium channels attractive targets for drug development. Dr. Christine Beeton, associate professor of Molecular Physiology and Biophysics, and her team at Baylor College of Medicine aim to identify and target potassium channels for chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, asthma, and myotonic dystrophy type I.

RA is a chronic inflammatory disease that affects 1.3 million people in the United States and there is no cure at this time. Current therapeutic approaches target the immune response. However, these drugs can induce severe side effects associated with immunosuppression that limit their long-term use and are inappropriate for patients with chronic infections. Therefore, novel therapies that target non-immune pathways are highly desired and would be of great benefit to patients. Dr. Beeton’s group has conducted successful proof-of-concept studies on novel RA treatment.

Dr. Beeton’s team identified KCa1.1 as the major potassium channel in RA-activated fibroblast-like synoviocytes (RA-FLS). FLS are a cell type located inside joints in the synovial membrane of most joints, and play a key role in perpetuating inflammation and contributing to cartilage destruction in RA. Treatment of RA-FLS with paxilline (PAX), a specific KCa1.1 small molecule inhibitor, significantly inhibits the proliferation and invasion of RA-FLS. Furthermore, targeting of this channel halts the progression of RA in an animal model. Utilizing a combinatorial approach of chemical synthesis, electrophysiology, and pharmacokinetics, the Beeton group, in collaboration with the Horrigan and Pedersen groups at BCM, is currently developing a targeted drug delivery system for PAX that can be used therapeutically to inhibit RA-FLS in inflamed joints.

In addition, Dr. Beeton previously made significant breakthroughs to target voltage-gated potassium channels in T-cell mediated autoimmune diseases, including multiple sclerosis and its animal model counterpart, experimental autoimmune encephalomyelitis (EAE).

Applications/Advantages

• New therapies that target potassium channels in chronic inflammation disease can be an alternative strategy to immunosuppression or co-administered with current treatments

• Potassium channel modulators are already clinically used as drugs for the treatment of type-2 diabetes and cardiac arrhythmia, supporting its safety and efficacy

• The primary investigator has more than a decade of research experience on potassium channels and their impact on autoimmune chronic inflammatory diseases

• Expertise in potassium channel blockers and autoimmune diseases provides a scientific framework for extending drug design beyond RA

• Comprehensive, multidisciplinary drug design, evaluation, optimization strategy in collaboration with other leading experts in the field

• Previous research findings have been published in numerous high-profile scientific journals and cited by numerous colleagues in the field

BLG Project Manager

Terese Rakow, Ph.D. (trakow@bcm.edu)