C, ELN1 iPSCs differentiated in vitro into all 3 germ layers. response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates experienced limited efficacy. Conclusions: Everolimus caused the most consistent improvement SEL120-34A in SMC differentiation, proliferation and in SMC function in patients with both Rabbit Polyclonal to GPR132 syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy. gene cause nonsyndromic SVAS, that is, SVAS without other systemic manifestations. The arterial narrowing often recurs despite surgery,3,4 and you will find no drugs clinically approved to treat this condition. Novel therapies are being tested in animal models and human cells as was recently reviewed.5 A recent small clinical trial evaluating minoxidil treatment on patients with WS reported no positive improvement in vascular phenotype.6 Our goal was to find targeted therapies that can rescue the abnormal vascular phenotype in SEL120-34A patients with elastin insufficiency (EI) using drugs approved by the Food and Drug Administration for other indications as a potential drug repurposing strategy. Although mouse models of EI have greatly improved our overall understanding of elastin signaling, there are limitations in their use in drug screens. on a SEL120-34A bacterial artificial chromosome recapitulates aortic thickening with heterozygosity suggesting that the human and mouse elastin gene, and elastin synthesis, are not regulated equivalently in the developing aorta, and highlights the need for human-relevant models.9C11 Patient induced pluripotent stem cells (iPSCs) provide human-relevant models while retaining the genetic background of the patient and provide a noninvasive and renewable cell source for study of phenotype and drug responses. Importantly, for the study of EI, the use of patient cells that still carry a functioning copy of the gene facilitates the screening of drugs that promote elastin transcription. Human iPSCs have been widely used to study the function of susceptible genes in a variety of diseases, including cardiovascular diseases.12C15 The use of iPSCs also offers a highly useful platform for drug screening because of their potential for replicating in vivo drug safety and efficacy.16C19 Human iPSCs can successfully be differentiated into vascular SMCs with efficiencies exceeding 80%,20 and their functional properties can be studied as they respond to vasoactive agonists.21 SMCs derived from patient iPSCs have been used to model vascular disease, such as WS, SVAS, hypertension, Marfan and Hutchinson-Gilford Progeria syndromes.22C26 These iPSC-SMCs recapitulated the pathological phenotype of each disease and identified novel targets for treatment.22,23,25 In our previous report, we recapitulated the disease phenotype of EI using patient iPSC-derived SMCs from a single patient with WS. The SMCs were hyperproliferative, poorly differentiated, and poorly contractile compared with healthy control cells. The antiproliferative mTOR (mammalian target of rapamycin) inhibitor rapamycin rescued the differentiation and proliferation defects SEL120-34A but did not improve contractile properties.22 The goal of the current study was to identify one or more drug classes that would rescue not just the phenotypic abnormalities but also functional abnormalities in the SMCs of patients with WS as well as those with mutations. We generated iPSCs from 2 additional patients with WS and 2 patients with heterozygous mutations, all of whom experienced infantile-onset severe disease. We analyzed the effect of 14 candidate drugs on SMC differentiation, proliferation, and calcium flux. Our results showed that drugs belonging to the class.