Ion Channel Therapeutics
CyThera Pharmaceuticals is developing new therapeutics against cancer, stroke and immune disease. Medical research at CyThera is focused on ion channels, which are proteins located in the membrane of the cells of our body. They possess a central pore that allows the passage of charged ions across the plasma membrane when the channel is opened by an appropriate stimulus. Through ion channels, cells control the passage of nutrients such as calcium (Ca²⁺), sodium (Na⁺), potassium (K⁺) and other ions. The concentration of these ions is critically important in regulating many physiological functions of the cells in our body. Consequently, ion channels represent an important class of targets for pharmaceutical intervention in a broad range of disease areas. CyThera is particularly interested in targeting ion channels in immune cells, thereby attenuating the activity of immune cells that underly autoimmune diseases.
Ion Channels in Lymphocytes
Ion channels play a central role in the activation of T lymphocytes following encounters with foreign or self antigens. During T cell activation, the cytosolic calcium concentration changes in an oscillatory fashion, driven by initial release of Ca²⁺ from intracellular stores and followed by store-operated Ca²⁺ entry. These Ca²⁺ oscillations are orchestrated by variations in membrane potential through the interplay of well-defined ion channels that allow Ca²⁺ influx across the plasma membrane (mediated by store-operated CRAC channels), membrane depolarization through Na⁺ influx (mediated by the Ca²⁺-activated cation channel TRPM4), and membrane hyperpolarization through K⁺ efflux (mediated by potassium channels Kv1.3 and IKCa3.1). Importantly, K⁺ channels contribute to Ca²⁺ entry by hyperpolarizing the cell membrane potential and enhancing the driving force for Ca²⁺ entry through CRAC channels. The elevation in Ca²⁺ promotes the formation of Ca²⁺-calmodulin complexes that activate the protein phosphatase calcineurin, which then dephosphorylates the nuclear factor of activated T cells (NFAT) and permits its translocation to the nucleus, where it stimulates transcription of IL-2 mRNA, thus promoting cytokine production and T cell proliferation.
After initial exposure to antigens, naïve T cells proliferate and differentiate into effector T cells that infiltrate inflamed tissues and destroy invading microorganisms or self-antigens as the case may be. Following this initial amplification, most effector T cells undergo apoptotic cell death, but leave behind a population of antigen-experienced effector memory T cells (TEM) that can vigorously respond to a second antigen challenge. Notably, the vast majority of TEM are resident in the skin and these cells become a liability if they respond to auto-antigens or in graft-versus-host reactions. The role of such auto-reactive TEM is well established in the pathogenesis of a variety of autoimmune diseases including psoriasis, multiple sclerosis, diabetes type1, rheumatoid arthritis, inflammatory bowel disease (Crohn’s Disease) and others as well as in rejection of cell, skin, and solid organ transplants.
Interestingly, effector memory T cells are characterized by substantial upregulation of Kv1.3 channel expression compared to naïve or effector T cells and, as a result, this channel becomes the predominant mechanism for cell hyperpolarization and driving force for Ca²⁺ influx in these cells. Inhibition of Kv1.3 causes membrane depolarization, inhibition of Ca²⁺ entry, suppression of Ca²⁺ oscillations, and attenuation of TEM activation while leaving other T-cell populations largely unaffected. This promotes targeted and selective suppression of disease-relevant T cells without causing generalized immunosuppression. CyThera is developing a potent and selective inhibitor of Kv1.3 channels to inhibit the activity of auto-reactive TEM.
Interestingly, effector memory T cells are characterized by substantial upregulation of Kv1.3 channel expression compared to naïve or effector T cells and, as a result, this channel becomes the predominant mechanism for cell hyperpolarization and driving force for Ca²⁺ influx in these cells. Inhibition of Kv1.3 causes membrane depolarization, inhibition of Ca²⁺ entry, suppression of Ca²⁺ oscillations, and attenuation of TEM activation while leaving other T-cell populations largely unaffected. This promotes targeted and selective suppression of disease-relevant T cells without causing generalized immunosuppression. CyThera is developing a potent and selective inhibitor of Kv1.3 channels to inhibit the activity of auto-reactive TEM.
