CuriBio's ComboMat is a combinatorial maturation platform that leverages NanoSurface™ Technology, media factors, and a gene expression-regulating microRNA (miR) formula to synergistically advance the maturation of hiPSC-CMs. ComboMat treated cardiomyocytes exhibit enhanced structural, functional, electrophysiological, and metabolic development.

ComboMat Includes a Proprietary Cocktail of microRNAs

The proprietary miR formula included in the ComboMat protocol specifically targets key pathways that drive cardiac-specific functional development, and can be applied to any hiPSC-CM cell line. ComboMat treated cells result in more human adult-like structural, functional, metabolic, and functional maturation.

Key Characteristics

ComboMat Drives iPSC-CM Maturation and Functional Development

• Structure - Increased sarcomere length and width, cell area, and more physiological cell aspect ratio.

• Electrophysiology - Exhibit longer field potential durations as measured by MEA, and lower resting beat rates than control iPSC-CMs.

• Metabolism - Enhanced metabolic developmental profiles, including a switch from glucose metabolism to fatty acid metabolism.

• Function - Generate more contractile force than control iPSC-CMs.

ComboMat hiPSC-CMs are able to accurately predict the cardiotoxicity of known high-risk drugs such as Bepridil, which the same untreated hiPSC-CMs fail to do so. In an MEA-based electrophysiology study, iPSC-CMs treated with 1 µM Bepridil exhibited clear EAD arrhythmic events in LEAP signals.

Application

Enable Creation of Well-Stratified Models of Human Disease

Phenotypic stratification of disease models provides a platform for the discovery and efficacy screening of new therapeutics.

Metabolic Disease

ComboMat drives iPSC-CMs toward the ability to metabolize fatty acids, a hallmark of metabolic maturity in adult cardiomyocytes. In a model of mitochondrial trifunctional protein deficiency, wild type ComboMat iPSC-CMs showed an enhanced ability to metabolize fatty acids in a SeaHorse palmitate assay, while both ComboMat mutant iPSC-CMs and wild type iPSC-CMs that did not receive ComboMat treatment did not. Only cell models that received ComboMat treatment were able to stratify the healthy metabolic phenotype from the disease phenotypes. ComboMat mutant cells exhibited proton leak, a phenotype that was rescued after treatment with SS-31 (Elamipretide).

 

Duchenne Muscular Dystrophy (DMD) Associated Cardiomyopathy

In a ComboMat iPSC-CM model of DMD Associated Cardiomyopathy, DMD mutant iPSC-CMs showed significantly higher cytosolic Ca2+ levels and significantly higher beat rate variability than wild type iPSC-CMs. DMD mutant and wild type iPSC-CMs that did not receive ComboMat treatment failed to show stratification of these key disease phenotypes. Treatment with Sildinafil failed to rescue the proarrhythmic phenotype, matching known clinical results.

 

 

 

 

Read papers on ComboMat:

TFPa/HADHA is Required for Fatty Acid Beta-oxidation and Cardiolipin Re-modeling in Human Cardiomyocytes – Miklas et al.

Published in Nature Communications

 

Engineered Developmental Niche Enables Predictive Phenotypic Screening in Human Dystrophic Cardiomyopathy – Macadangdang et al.