Related Experiment Video
Updated: Sep 8, 2025
Microfluidics in Assessing Platelet Function
Published on: November 8, 2024
CIC-39Na reverses the thrombocytopenia that characterizes tubular aggregate myopathy
Celia Cordero-Sanchez1, Emanuela Pessolano1, Beatrice Riva1
1Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
Insights
Store-operated calcium entry inhibitors like CIC-39Na can treat rare myopathies. This study shows CIC-39Na restores platelet counts and reduces bleeding in mice with STIM1 mutations.
Area of Science:
- Cellular Biology
- Hematology
- Pharmacology
Background:
- Store-operated calcium entry (SOCE) is crucial for cellular calcium homeostasis.
- Gain-of-function mutations in STIM1 and ORAI1 cause ultra-rare tubular aggregate myopathies with muscle weakness and thrombocytopenia.
- Current treatments for these conditions are lacking.
Purpose of the Study:
- To investigate the therapeutic potential of a SOCE inhibitor, CIC-39Na, for thrombocytopenia associated with STIM1 gain-of-function mutations.
- To elucidate the mechanisms by which CIC-39Na affects platelet count and function in a STIM1 mutant mouse model.
Main Methods:
- Utilized a mouse model with the STIM1 p.I115F mutation, which exhibits muscle weakness and thrombocytopenia.
- Administered CIC-39Na, a novel store-operated calcium entry inhibitor, to the STIM1 mutant mice.
- Assessed platelet counts, bleeding times, platelet clearance, and intracellular calcium levels.
Main Results:
- CIC-39Na treatment effectively restored platelet numbers in STIM1 p.I115F mice.
- Abnormal bleeding, characteristic of the disease model, was counteracted by CIC-39Na.
- Treatment normalized platelet clearance and reduced elevated basal platelet cytosolic calcium levels.
Conclusions:
- CIC-39Na demonstrates significant therapeutic potential for treating thrombocytopenia in STIM1-related myopathies.
- Targeting store-operated calcium entry offers a promising pharmacological strategy for these rare diseases.
- Further research may lead to clinical applications for patients with tubular aggregate myopathies.
Abstract:
Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.
Related Concept Videos
01:15Drugs that Stabilize Microtubules
01:10Drugs that Destabilize Microtubules