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Next-generation calcium channel modulators

下一代钙通道调节剂

基本信息

批准号：
10526425
负责人：
Ivy E Dick
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-20 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526425
关键词：
Action Potentials Adult Alternative Splicing Antisense Oligonucleotides Biophysics Bypass Calcium Calcium Channel Cardiac Cavia Cells Cessation of life Clinical Complement Computer Models Cues DNA Sequence Alteration Developmental Delay Disorders Dihydropyridines Disease Electrophysiology (science)Exclusion Exons Genetic Diseases Human Image Ion Channel Length Long QT Syndrome Maps Molecular Biology Muscle Cells Mutation Neurologic Neurologic Deficit Optics Patients Pattern Pharmaceutical Preparations Phenotype Physiological Physiology Play Point Mutation Predisposition Process Protein Splicing Proteins RNA Splicing Regulation Risk Role System Techniques Testing Therapeutic Timothy syndrome Variant Ventricular Verapamil Work autism spectrum disorder cell type channel blockers common treatment conventional therapy design experimental study human disease hypertension treatment improved individual response induced pluripotent stem cell derived cardiomyocytes insight mutant next generation novel novel strategies novel therapeutic intervention novel therapeutics patch clamp patient population patient response patient subsets response small molecule success tool treatment strategy voltage

项目摘要

CaV1.2 Ca2+ channels are critical conduits for Ca2+ entry into a diverse array of excitable cells. As such, these channels must be precisely tuned to function appropriately for each cell type, and in response to varying physiological cues. To this end, the channels employ multiple mechanisms of regulation, including alternative splicing, voltage dependent inactivation and calcium dependent inactivation. However, a growing number of mutations have been identified in CaV1.2, leading to severe phenotypes including neurological deficits, long-QT syndrome (LQTS), and death. Timothy Syndrome (TS) represents one such class of mutations, in which a single point mutation within CaV1.2 leads to a severe multisystem disorder characterized by developmental delays, autism and profound LQTS. Many of the known TS mutations have been shown to decrease channel inactivation, implicating Ca2+ channel blockers (CCBs) as a promising treatment option. However, despite some modest success with verapamil, CCBs have had limited efficacy in treating TS. Here, we postulate that this lack of efficacy may be due to a differential effect of CCBs on mutant versus wild type CaV1.2, necessitating the exploration of alternative therapeutic options for these patients. We propose that manipulating CaV1.2 splicing represents just such an alternative strategy, with significant promise for the treatment of these patients. Specifically, as the majority of TS patients harbor a mutation within a mutually exclusive exon, we will design antisense oligonucleotides (AONs) targeted to the exon containing the mutation. As such, we expect to force the exclusion of the deleterious exon, induce inclusion of the unaffected alternate exon, and produce a fully functional alternate channel splice variant. Importantly, this strategy will bypass the current limitations of conventional therapies, providing significant clinical benefit for TS patients. Moreover, application of this technique to WT CaV1.2 channels may lead to promising new therapeutic insights within a broader population of patients. In particular, we will apply our splice modulating AONs to test the hypothesis that atypical splice patterns in some patients may render them more susceptible to detrimental cardiac effects of DHP treatment. Finally, as numerous genetic mutations occur within mutually exclusive exons, our application of AONs to TS will serve as a generalizable strategy applicable to numerous genetic mutations in a multitude of proteins. Overall, targeted manipulation of protein splicing represents a large and untapped opportunity, providing a path forward for treatment of a diverse array of diseases.

Ca2+通道是Ca2+进入多种可兴奋细胞的关键通道。因此，这些