Allogeneic fetal‐derived human neural stem cells (hfNSCs) that are under clinical evaluation for several neurodegenerative diseases display a favorable safety profile, but require immunosuppression upon transplantation in patients. Neural progenitors derived from patient‐specific induced pluripotent stem cells (iPSCs) may be relevant for autologous ex vivo gene‐therapy applications to treat genetic diseases with unmet medical need. In this scenario, obtaining iPSC‐derived neural stem cells (NSCs) showing a reliable “NSC signature” is mandatory. Here, we generated human iPSC (hiPSC) clones via reprogramming of skin fibroblasts derived from normal donors and patients affected by metachromatic leukodystrophy (MLD), a fatal neurodegenerative lysosomal storage disease caused by genetic defects of the arylsulfatase A (ARSA) enzyme. We differentiated hiPSCs into NSCs (hiPS‐NSCs) sharing molecular, phenotypic, and functional identity with hfNSCs, which we used as a “gold standard” in a side‐by‐side comparison when validating the phenotype of hiPS‐NSCs and predicting their performance after intracerebral transplantation. Using lentiviral vectors, we efficiently transduced MLD hiPSCs, achieving supraphysiological ARSA activity that further increased upon neural differentiation. Intracerebral transplantation of hiPS‐NSCs into neonatal and adult immunodeficient MLD mice stably restored ARSA activity in the whole central nervous system. Importantly, we observed a significant decrease of sulfatide storage when ARSA‐overexpressing cells were used, with a clear advantage in those mice receiving neonatal as compared with adult intervention. Thus, we generated a renewable source of ARSA‐overexpressing iPSC‐derived bona fide hNSCs with improved features compared with clinically approved hfNSCs. Patient‐specific ARSA‐overexpressing hiPS‐NSCs may be used in autologous ex vivo gene therapy protocols to provide long‐lasting enzymatic supply in MLD‐affected brains. Stem Cells Translational Medicine 2017;6:352–368

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The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.

Aim: To evaluate outcomes related to antiplatelet therapy in patients with ST-elevation myocardial infarction (STEMI) admitted to the San Gerardo Hospital in Monza, an extracorporeal membrane oxygenation (ECMO) reference center in the Monza-Brianza area. Methods: This retrospective study enrolled patients with STEMI hospitalized between 2013 and 2017. Results: This study included 653 patients (mean age: 67.5 years, 71% male). Across the study period, ticagrelor use showed consistent increases, from 22% of patients during 2013 to 85% in 2017. Cardiac arrest prehospitalization occurred in 100 patients (15.3%), either at home (n = 85, 13.0%) or during transfer (n = 15, 2.3%); 46 patients underwent ECMO for refractory cardiac arrest. Rates of 90-day survival (hazard ratio [HR]: 2.4, 95% confidence interval [CI]: 1.3-4.4, P = .004) and ST resolution (odds ratio [OR]: 2.5, 95% CI: 1.6-4.1, P = .000) were higher with ticagrelor than with other antiplatelet agents. When analyzed by each agent, patients on ticagrelor had longer survival (HR: 0.4, 95% CI: 0.2-0.8, P = .008) than patients on clopidogrel and more frequent ST resolution than those on clopidogrel or prasugrel (OR: 0.4, 95% CI: 0.2-0.7, P = .002 and OR: 0.4, 95% CI: 0.2-0.7, P = .006). There was no difference in mortality between ticagrelor and prasugrel. Conclusions: Changes in the treatment of high-risk patients with STEMI over time are in line with changes in treatment guidelines. In these patients, ticagrelor is associated with significantly improved 90-day mortality compared with clopidogrel.

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Sudden cardiac death (SCD) is a potentially fatal event usually caused by a cardiac arrhythmia, which is often the result of coronary artery disease (CAD). Up to 80% of patients suffering from SCD have concomitant CAD. Arrhythmic complications may occur in patients with acute coronary syndrome (ACS) before admission, during revascularization procedures, and in hospital intensive care monitoring. In addition, about 20% of patients who survive cardiac arrest develop a transmural myocardial infarction (MI). Prevention of ACS can be evaluated in selected patients using cardiac computed tomography angiography (CCTA), while diagnosis can be depicted using electrocardiography (ECG), and complications can be evaluated with cardiac magnetic resonance (CMR) and echocardiography. CCTA can evaluate plaque, burden of disease, stenosis, and adverse plaque characteristics, in patients with chest pain. ECG and echocardiography are the first-line tests for ACS and are affordable and useful for diagnosis. CMR can evaluate function and the presence of complications after ACS, such as development of ventricular thrombus and presence of myocardial tissue characterization abnormalities that can be the substrate of ventricular arrhythmias.