DeepNEU: Artificially Induced Stem Cell (aiPSC) and Differentiated Skeletal Muscle Cell (aiSkMC) Simulations of Infantile Onset POMPE Disease (IOPD) for Potential Biomarker Identification and Drug Discovery.

Sally Esmail,Wayne R Danter

doi:10.3389/fcell.2019.00325

Abstract

Infantile onset Pompe disease (IOPD) is a rare and lethal genetic disorder caused by the deletion of the acid alpha-glucosidase (GAA) gene. This gene encodes an essential lysosomal enzyme that converts glycogen to glucose. While enzyme replacement therapy helps some, our understanding of disease pathophysiology is limited. In this project we develop computer simulated stem cells (aiPSC) and differentiated skeletal muscle cells (aiSkMC) to empower IOPD research and drug discovery. Our Artificial Intelligence (AI) platform, DeepNEU v3.6 was used to generate aiPSC and aiSkMC simulations with and without GAA expression. These simulations were validated using peer reviewed results from the recent literature. Once the aiSkMC simulations (IOPD and WT) were validated they were used to evaluate calcium homeostasis and mitochondrial function in IOPD. Lastly, we used aiSkMC IOPD simulations to identify known and novel biomarkers and potential therapeutic targets. The aiSkMC simulations of IOPD correctly predicted genotypic and phenotypic features that were reported in recent literature. The probability that these features were accurately predicted by chance alone using the binomial test is 0.0025. The aiSkMC IOPD simulation correctly identified L-type calcium channels (VDCC) as a biomarker and confirmed the positive effects of calcium channel blockade (CCB) on calcium homeostasis and mitochondrial function. These published data were extended by the aiSkMC simulations to identify calpain(s) as a novel potential biomarker and therapeutic target for IOPD. This is the first time that computer simulations of iPSC and differentiated skeletal muscle cells have been used to study IOPD. The simulations are robust and accurate based on available published literature. We also demonstrated that the IOPD simulations can be used for potential biomarker identification leading to targeted drug discovery. We will continue to explore the potential for calpain inhibitors with and without CCB as effective therapy for IOPD.

Highlights

Infantile onset Pompe disease (IOPD) (OMIM 232300) is a rare but lethal glycogen storage disorder caused by either loss or reduced activity of the lysosomal enzyme acid alpha-1,4glucosidase (GAA, EC 3.2.1.20)
In our recently published research, we have introduced DeepNEU, a novel unsupervised deep-machine learning computational platform that enables the successful generation of artificially induced pluripotent stem cells, artificially induced neural stem cells and artificially induced cardiomyocytes (Danter, 2019)
The initial goal of this project was to first create a computer simulation of a human induced pluripotent stem cell and skeletal muscle cell models of Infantile onset POMPE disease (IOPD) and validate these models using the results published by Yoshida et al (2017) and others as described above

Summary

Introduction

Infantile onset Pompe disease (IOPD) (OMIM 232300) is a rare but lethal glycogen storage disorder caused by either loss or reduced activity of the lysosomal enzyme acid alpha-1,4glucosidase (GAA, EC 3.2.1.20). This ubiquitously expressed enzyme is responsible for the conversion of glycogen to glucose (Hers, 1963). GAA deficiency leads to glycogen accumulation in lysosomes and the cytoplasm, leading to compromised tissue function. Skeletal muscle and cardiac tissue are most commonly affected by GAA deficiency (Hers, 1963). IOPD affected infants present with a variety of abnormalities including loss of muscle tone, abnormal electrocardiogram, myocardial thickening, generalized weakness and hepatomegaly

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