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The Challenge of Bringing iPSCs to the Patient.

ABSTRACT: The implementation of induced pluripotent stem cells (iPSCs) in biomedical research more than a decade ago, resulted in a huge leap forward in the highly promising area of personalized medicine. Nowadays, we are even closer to the patient than ever. To date, there are multiple examples of iPSCs applications in clinical trials and drug screening. However, there are still many obstacles to overcome. In this review, we will focus our attention on the advantages of implementing induced pluripotent stem cells technology into the clinics but also commenting on all the current drawbacks that could hinder this promising path towards the patient.

SUBMITTER: Ortuno-Costela MDC

PROVIDER: S-EPMC6940848 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The Challenge of Bringing iPSCs to the Patient.

Ortuño-Costela María Del Carmen MDC Cerrada Victoria V García-López Marta M Gallardo M Esther ME

International journal of molecular sciences 20191213 24

The implementation of induced pluripotent stem cells (iPSCs) in biomedical research more than a decade ago, resulted in a huge leap forward in the highly promising area of personalized medicine. Nowadays, we are even closer to the patient than ever. To date, there are multiple examples of iPSCs applications in clinical trials and drug screening. However, there are still many obstacles to overcome. In this review, we will focus our attention on the advantages of implementing induced pluripotent s ...[more]

PMID: 31847153

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Project description:Canada must become proactive in addressing type 2 diabetes. With the second highest rate of diabetes prevalence in the developed world, the number of Canadians living with diabetes will soon reach epidemic levels. Against international comparisons, Canada also performs poorly with respect to diabetes-related hospitalizations, mortality rates, and access to medications. Diabetes and its comorbidities pose a significant burden on people with diabetes (PWD) and their families, through out-of-pocket expenses for medications, devices, supplies, and the support needed to manage their illness. Rising direct and indirect costs of diabetes will become a drain on Canada's economy and undermine the financial stability of our health care system. Canada's approach to diabetes medication assessment and funding has created a patchwork of medication access across provinces. Access to treatments for those who rely on public programs is highly restricted compared to Canadians with private drug plans, as well in contrast with public payers in other countries. Each person living with diabetes has different needs, so a "patient-centric" approach ensures treatment focused on individual circumstances. Such tailoring is difficult to achieve, with the linear approach required by public payers. We may be undermining optimal care for PWD because of access policies that are not aligned with individualized approaches - and increasing overall health care costs in the process. The scope of Canada's diabetes challenge demands holistic and proactive solutions. Canada needs to get out from "behind the eight ball" and get "ahead of the curve" when it comes to diabetes care. Improving access to medications is one of the tools for getting there. Canada's "call to action" for diabetes starts with effective implementation of existing best practices. A personalized approach to medication access, to meet individual needs and optimize outcomes, is also a key enabler. PWD and prescribers need reimbursement approaches that allow them to use existing tools (ie, medications and supplies) to manage diabetes in a timely manner and to avoid and/or delay major downstream complications.

Project description:Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging owing to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle, which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2, encoding plakophilin-2 (ref. 9). The median age at presentation of ARVD/C is 26?years. We used previously published methods to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations. Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased ?-catenin activity in cardiogenic conditions; yet, these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPAR-?) activation underlie the pathogenesis of ARVD/C. By co-activating normal PPAR-alpha-dependent metabolism and abnormal PPAR-? pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in vitro model within 2?months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC-CMs. iPSC-CMs with a homozygous PKP2 mutation also had calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism has a critical role in establishing an adult-onset disease model using patient-specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies.

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The Challenge of Bringing iPSCs to the Patient.

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The Challenge of Bringing iPSCs to the Patient.

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