Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

Beeton, Christine; Wulff, Heike; Standifer, Nathan; Azam, Philippe; Mullen, Katherine M.; Pennington, Michael W.; Kolski-Andreaco, Aaron; Wei, Eric; Grino, Alexandra; Counts, Debra; Wang, Ping H.; LeeHealey, Christine J.; Andrews, Brian S.; Sankaranarayanan, Ananthakrishnan; Homerick, Daniel; Roeck, Werner W.; Tehranzadeh, Jamshid; Stanhope, Kimber L.; Zimin, Pavel I.; Havel, Peter J.; Griffey, Stephen M.; Knaus, Hans Guenther; Nepom, Gerald T.; Gutman, George A.; Calabresi, Peter A.; Chandy, K. George

doi:10.1073/pnas.0605136103

Cited by 481 publications

(795 citation statements)

References 47 publications

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“…Pharmacokinetic studies using UPLC/MS have shown that total PAP‐1 brain concentrations peak between 2 and 10 μ mol/L at 2 h after administration of 10 or 40 mg/kg but that brain concentrations for most of the 12‐h time period between drug administrations are in the range of 200 nmol/L to 1 μ mol/L. Considering PAP‐1's plasma protein binding of 98%, these total concentrations translate to effective free concentrations of 40–200 nmol/L at the C max and of 4–20 nmol/L for most of the time in this study 4, 23. We therefore believe that Kv1.2 inhibition is not likely to significantly contribute to the effects of PAP‐1.…”

Section: Discussionmentioning

confidence: 78%

“…In addition, K V 1.3 blockade seems to be relatively safe and well tolerated. Toxicity studies with PAP‐1 and the peptidic K V 1.3 blocker ShK‐186 have so far not revealed any toxicity despite 6 months or 28 days of continuous administration in rats or rhesus macaques 4, 8. PAP‐1 has further completed IND‐enabling toxicity studies, while ShK‐186 has passed both IND toxicity studies and Phase‐1 safety studies without any adverse findings 6, 9…”

Section: Discussionmentioning

confidence: 99%

“…After the channel was cloned, the pharmaceutical industry initiated Kv1.3 discovery programs in the mid‐1990s but largely failed to identify compounds that were suitable for development 2. Interest in Kv1.3 afterward waned but revived following reports from our group that Kv1.3 is overexpressed in activated CCR7 − effector memory T‐cells (T EM ) and that Kv1.3 blockers therefore constitute immunomodulators rather than general immunosuppressants 3, 4, 5. Subsequent proof‐of‐concept animal studies demonstrated that the Kv1.3 blocking sea anemone Stichodactyla helianthus peptide ShK and its derivatives treat rat models of multiple sclerosis and rheumatoid arthritis,4, 5, 6 while our small molecule Kv1.3 blocker PAP‐1 prevents autoimmune diabetes4 in rats and treats psoriasis in a mouse xenograft model 7.…”

Section: Introductionmentioning

confidence: 99%

“…PAP‐1 is currently the most potent and selective small molecule Kv1.3 blocker available. It inhibits Kv1.3 with an IC 50 of 2 nmol/L,22 has a half‐life of 3 h in rodents, is orally available, brain penetrant and does not exhibit any long‐term toxicity in rodents or primates 4, 8, 23…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInhibitors of the voltage‐gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up‐regulated on “M1‐like” microglia, we here tested the therapeutic hypothesis that the brain‐penetrant small‐molecule Kv1.3‐inhibitor PAP‐1 reduces secondary inflammatory damage after ischemia/reperfusion.MethodsWe studied microglial Kv1.3 expression using electrophysiology and immunohistochemistry, and evaluated PAP‐1 in hypoxia‐exposed organotypic hippocampal slices and in middle cerebral artery occlusion (MCAO) with 8 days of reperfusion in both adult male C57BL/6J mice (60 min MCAO) and adult male Wistar rats (90 min MCAO). In both models, PAP‐1 administration was started 12 h after reperfusion.ResultsWe observed Kv1.3 staining on activated microglia in ischemic infarcts in mice, rats, and humans and found higher Kv1.3 current densities in acutely isolated microglia from the infarcted hemisphere than in microglia isolated from the contralateral hemisphere of MCAO mice. PAP‐1 reduced microglia activation and increased neuronal survival in hypoxia‐exposed hippocampal slices as effectively as minocycline. In mouse MCAO, PAP‐1 dose‐dependently reduced infarct area, improved neurological deficit score, and reduced brain levels of IL‐1β and IFN‐γ without affecting IL‐10 and brain‐derived nerve growth factor (BDNF) levels or inhibiting ongoing phagocytosis. The beneficial effects on infarct area and neurological deficit score were reproduced in rats providing confirmation in a second species.InterpretationOur findings suggest that Kv1.3 constitutes a promising therapeutic target for preferentially inhibiting “M1‐like” inflammatory microglia/macrophage functions in ischemic stroke.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Chen

Nguyen

Maezawa

et al. 2017

Ann Clin Transl Neurol

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“…Autoreactive CD4+ T cells in T1D display characteristics associated with prior antigen experience or chronic activation, including cell surface molecules CD45RO [11;12], Kv1.3 [13], and OX40 [14], and can be activated without co-stimulatory signals [15]. These maturation characteristics distinguish autoreactive cells in T1D subjects from similar, potentially autoreactive, naïve cells, which are present in normal individuals [11][12][13], and identify potential biomarkers that may correlate with clinical status.…”

Section: Discussionmentioning

confidence: 99%

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Laughlin

Burke

Pugliese

et al. 2008

Clinical Immunology

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CD4+ T cells specific for the diabetes-associated autoantigen GAD65 were analyzed using peripheral blood samples after pancreas transplantation in subjects with T1D with clinical evidence of recurrent autoimmune diabetes. MHC class II tetramers facilitated the identification and cloning of antigenspecific autoreactive cells, which were found at several time points over a multiyear span, in spite of chronic immunosuppression of the subjects. Comparisons of TCR clonotypes by cDNA sequencing revealed that identical T cells were present in the circulation, separated by long time intervals, consistent with a persistent memory response associated with recurrent autoimmunity.

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Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K⁺) channel activity

et al. 2019

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A causal relationship exists between macrophage cholesterol levels and inflammation, for example, Interleukin‐1β (IL‐1β) secretion. A decrease in intracellular K+ is essential for inflammasome activation/IL‐1β secretion and, herein, we examined the hypothesis that cellular cholesterol affects K+‐channel activity and K+‐efflux using mouse peritoneal macrophages (MPMs) and human/THP1 macrophages. An increase in cellular cholesterol led to a significant increase in K+ currents (> 350% in both MPM and THP1). Enhancing cholesterol efflux returned K+ currents back to basal levels with corresponding increase in intracellular K+ (11.2–14.5%) and reduced IL‐1β secretion (32–62%). These data demonstrate a novel mechanism by which cellular cholesterol modulates inflammation/inflammasome via regulation of K+‐channel activity and intracellular K+ levels. Attenuation of IL‐1β secretion by Nateglinide/Repaglinide further suggests involvement of Kir6 channels.

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Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

Cited by 481 publications

References 47 publications

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K⁺) channel activity

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Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases

Cited by 481 publications

References 47 publications

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K+) channel activity

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Product

Resources

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Regulation of interleukin‐1 beta secretion from macrophages via modulation of potassium ion (K⁺) channel activity