The Kv1.3 potassium channel as a target for multip

Target of the Month, (from TherapeuticAdvances, August, 2003): As research into ion channels continues to identify novel targets for multiple and diverse diseases, therapeutic successes surrounding the development of channel modulators will boom (for a full overview of this area, Click here to access Ion Channels as Therapeutic Targets for Multiple Diseases). Numerous companies are engaged in R&D programs involving ion channels in a number of areas, including asthma, inflammation, arrhythmia and CNS disorders, and drugs targeting ion channels already generate over $6 billion in sales per annum. Despite their remarkable physiological value, ion channels have remained a relatively unexploited therapeutic target, especially in comparison to G-protein coupled receptors or kinases. This situation is rapidly changing with the appearance of improved screening tools as well as highly targeted libraries of candidate channel modulators (see for example the Potassium channel enterprise library recently featured by LeadDiscovery).

One channel that is receiving growing interest in the scientific community is the voltage-gated K + channel, Kv1.3. This channel is one of two potassium channels expressed by human T lymphocytes that are involved in proliferation and cytokine secretion (the other is the calcium-activated K + channel IKCa1). Researchers at George Chandy’s group at the University of California in collaboration with French field leaders have recently reported that myelin-reactive encephalitogenic rat T cells expressed unusually high numbers of Kv1.3 channels following antigenic stimulation (Beeton et al, 2001). These cells exhibit a memory phenotype and are believed to contribute to the inflammatory attack on the central nervous system in this model for multiple sclerosis (MS). Indeed adoptive transfer of these T cells induced multiple sclerosis-like inflammation in naïve rats, an effect that was reduced by Kv1.3 blockade. The search for Kv1.3 blockers or molecules able to prevent channel expression could therefore provide novel anti-inflammatory molecules. Merck researchers have recently published a series of Kv1.3 channel inhibitors for the potential treatment of autoimmune diseases and it therefore appears that the therapeutic potential of targeting this channel is beginning to be realized.

Dr Chandy’s group has recently published further important proof of concept data surrounding the development of Kv1.3 blockers. Specifically they used the patch-clamp technique in combination with fluorescence microscopy and flow cytometry to determine whether the distinctive Kv1.3highIKCa1low channel pattern is found in human memory cells, and in particular in myelin-reactive T cells from MS patients.

In humans, two subsets of memory T lymphocytes, central memory T cells and effector memory T cells, have been described based on the expression of the chemokine receptor CCR7 and the phosphatase CD45RA. Naïve cells, which express both markers, and central memory T cells, which express only CCR7, require antigen priming in lymph nodes before they migrate to inflammatory sites. In contrast terminally differentiated effector memory T cells, which express neither marker rapidly enter inflamed tissues, produce copious amounts of IFN-gamma and IL-4, and exhibit immediate effector function. In their JCI paper, Dr Chandy’s group demonstrate that the Kv1.3highIKCa1low channel phenotype is found exclusively in activated human effector memory T cells, whereas naive and central memory T cells remain Kv1.3low and upregulate IKCa1 upon activation. Myelin-reactive T cells from MS patients are predominantly effector memory T cells and exhibit the Kv1.3highIKCa1low channel pattern after activation with myelin antigens, suggesting that they have undergone multiple rounds of antigenic stimulation during the course of disease. A high-affinity Kv1.3 inhibitor specifically suppressed proliferation of effector memory T cells at picomolar concentrations without persistently affecting the function of naive or central memory T cells lymphocytes. Selective inhibition of Kv1.3 channels in effector memory T cells may therefore be a potential approach for therapy of MS and other T cell-mediated autoimmune disorders. This approach would be relatively specific in that only effector memory T cells would be targeted leaving other immunocytes unaffected. It should however be noted that activated effector memory T cells are important in the control of chronic infectious agents and in the efficacy of vaccines. Therefore Kv1.3 inhibitors may present a certain level of risk with respect to lowered immunity however this risk is likely to be considerably less than that associated with immunomodulators currently used for therapy.

MS is a slowly progressive CNS disease characterized multiple and varied neurologic symptoms and signs, usually with remissions and exacerbations. MS affects more than 350,000 persons in the US. Around the world, northern Europe and the northern tier of the United States have the highest prevalence, with rates exceeding 30 cases per 100,000 population. About 25% of people with MS become wheelchair-bound, while more than 70% eventually have limited capacity. The MS market currently stands at about $2 billion in global pharma sales and is second only to Alzheimer's disease with respect to market growth (for a full evaluation of therapeutic and commercial opportunities surrounding neurodegenerative disorders click here). Hence pharmaceutical interest in identifying an effective treatment of MS is considerable. The development of Kv1.3 channel inhibitors is therefore eagerly awaited.

Adapted from Wulff et al, J Clin Invest. 2003 Jun 1;111(11):1703-1713

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