Personalised medicines for familial hypercalcemia and hyperparathyroidism

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Loss-of-function mutations in the calcium-sensing receptor (CASR) lead to mineral metabolism disorders and increase disease risk.
• Current treatments like cinacalcet are only partially effective for patients with CASR mutations.

Purpose of the Study:

• To compare the efficacy of existing CASR activators (cinacalcet, evocalcet, etelcalcetide) and a novel PAM (MIPS-VD-836-108) on clinically relevant CASR mutations.
• To evaluate the potential of these compounds in rescuing impaired intracellular calcium mobilization and cell surface expression caused by CASR mutations.

Main Methods:

• HEK293 cells expressing CASR mutations were treated with cinacalcet, evocalcet, etelcalcetide, and MIPS-VD-836-108.
• Assays measured intracellular calcium (Ca2+i) mobilization and cell surface receptor expression.

Main Results:

• Cinacalcet, MIPS-VD-836-108, and evocalcet partially rescued signaling in cell surface-expressed mutants; etelcalcetide was ineffective.
• Cinacalcet and evocalcet restored expression of the R680H mutant, but not I81K, C582R, or CASRexon 5 deletion mutants.
• No compound effectively rescued expression of all tested mutants.

Conclusions:

• Specific CASR activators may benefit certain patients with CASR mutations.
• A significant portion of patients may remain unresponsive to current CASR activators.
• Development of next-generation drugs is crucial to address both signaling and expression defects in mutant CASRs.