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Development of Novel Therapies for Marfan Syndrome using a Human iPSC-disease model



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McNamara, Madeline Elizabeth Odile 


Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1, a matrix component encoded by the gene FBN1, with pleiotropic manifestations including severe cardiovascular complications, such as aortic aneurysms and dissection. Current treatments focus on surgically removing the aneurysm or on minimising aortic wall stress by controlling haemodynamics, but neither of these strategies tackle the underlying pathology. Although MFS is caused by fibrillin-1 mutations, it remains unclear how these lead to the pleiotropic manifestations seen in patients. Defective fibrillin-1 is thought to lead to excessive release of TGF-β in the extracellular environment, which will increase TGF-β signalling activity. Substantial efforts observed that angiotensin II receptor (AngIIR) blockade is able to rescue promiscuous TGF-β signalling and aortic complications in a MFS mouse model (Habashi et al. 2006). However, results in clinical trials have been disappointing (Lacro et al. 2014) and it is increasingly apparent that there is a need to develop better disease models for MFS to improve therapy development. In addition to abnormal TGF-β signalling, matrix degradation is a likely crucial component for pathology development as most clinical studies show extracellular matrix degradation and increased matrix proteolytic enzyme levels in diseased aortas (Chung et al. 2007; Xiong et al. 2012). In this work, I speculate that there are multiple disease perturbations downstream of the FBN1 mutations and that there is a need to develop novel strategies to identify new putative disease mediators and signalling pathways that participate in the pathogenicity. Here, I use a patient iPSC-derived in vitro disease model that recapitulates the complexity of the patient abnormalities (Granata et al. 2017) to develop two potential therapeutic strategies (i) directly interfering at the level of the pathological mutation using an exon skipping approach and (ii) designing an unbiased phenotypic drug screen to identify putative compounds able to rescue abnormal proteolysis in our disease model. These complementary techniques will enable the identification of novel disease-causing pathways and offer strategies for clinical intervention using our in vitro disease model as a platform for drug discovery.





Sinha, Sanjay


iPSC, marfan syndrome, aortic disease, drug-screen


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
BHF Regenerative Medicine