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Rochester, MN, United States

Murthy V.,Molecular Therapeutics | Reyes S.,Marriott Heart Disease Research Program | Geng L.,Molecular Therapeutics | Gao Y.,Molecular Therapeutics | Brimijoin S.,Molecular Therapeutics
Journal of Pharmacology and Experimental Therapeutics | Year: 2016

Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics. Source

Thatava T.,Rochester College | Kudva Y.C.,Rochester College | Edukulla R.,Rochester College | Squillace K.,Rochester College | And 7 more authors.
Molecular Therapy | Year: 2013

Nuclear reprogramming of adult somatic tissue enables embryo-independent generation of autologous, patient-specific induced pluripotent stem (iPS) cells. Exploiting this emergent regenerative platform for individualized medicine applications requires the establishment of bioequivalence criteria across derived pluripotent lines and lineage-specified derivatives. Here, from individual patients with type 1 diabetes (T1D) multiple human iPS clones were produced and prospectively screened using a battery of developmental markers to assess respective differentiation propensity and proficiency in yielding functional insulin (INS)-producing progeny. Global gene expression profiles, pluripotency expression patterns, and the capacity to differentiate into SOX17-and FOXA2-positive definitive endoderm (DE)-like cells were comparable among individual iPS clones. However, notable intrapatient variation was evident upon further guided differentiation into HNF4α-and HNF1β-expressing primitive gut tube, and INS-and glucagon (GCG)-expressing islet-like cells. Differential dynamics of pluripotency-associated genes and pancreatic lineage-specifying genes underlined clonal variance. Successful generation of glucose-responsive INS-producing cells required silencing of stemness programs as well as the induction of stage-specific pancreatic transcription factors. Thus, comprehensive fingerprinting of individual clones is mandatory to secure homogenous pools amenable for diagnostic and therapeutic applications of iPS cells from patients with T1D. © The American Society of Gene & Cell Therapy. Source

Arrell D.K.,Marriott Heart Disease Research Program | Arrell D.K.,Molecular Therapeutics | Arrell D.K.,Heart Genetics | Terzic A.,Marriott Heart Disease Research Program | And 2 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

Systems biology provides a platform for integrating multiple components and interactions underlying cell, organ, and organism processes in health and disease. Beyond traditional approaches focused on individual molecules or pathways, bioinformatic network analysis of high-throughput data sets offers an opportunity for integration of biological complexity and multilevel connectivity. Emerging applications in rational drug discovery range from targeting and modeling disease-corrupted networks to screening chemical or ligand libraries to identification/validation of drug-target interactions for improved efficacy and safety. © 2010 American Society for Clinical Pharmacology and Therapeutics. Source

Olson T.M.,Marriott Heart Disease Research Program | Olson T.M.,Mayo Medical School | Terzic A.,Marriott Heart Disease Research Program
Pflugers Archiv European Journal of Physiology | Year: 2010

Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATPsensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potentialdependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in K ATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, K ATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-atlarge and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within K ATP channel genes and the spectrum of genotype-phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy. © The Author(s) 2009. Source

Behfar A.,Marriott Heart Disease Research Program | Yamada S.,Marriott Heart Disease Research Program | Crespo-Diaz R.,Marriott Heart Disease Research Program | Nesbitt J.J.,Marriott Heart Disease Research Program | And 7 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction. Background: Adult stem cells, delivered in their nave state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome. Methods: hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1, bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points. Results: Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helixloophelix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. Conclusions: Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy. © 2010 American College of Cardiology Foundation. Source

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