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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Wang et al. (2014) generated human pluripotent stem cell-based model of the congenital Long QT syndrome (LQTS; QT refers to an interval in an electrocardiogram; a retarded potassium current leads to a prolonged action potential), a disease that predisposes patients to cardiac arrhythmic disease, tantamount to life-threatening ventricular arrhythmias and sudden cardiac death and is caused among others by mutations in the potassium channels, KCNQ1 (LQTS1) and KCNH2 (LQTS2). Theses ion channel genes with dominant negative mutations were integrated into AAVS1 locus using ZFN technology and stably introduced into human ESCs or iPSCs. The transgenic cells were differentiated into cardiomyocytes (CMs), resulting in ZFN-edited iPSC-CMs that were tested for with the unedited cells serving as the isogenic control. The authors demonstrated that iPSC-CMs are characterized by a prolonged action potential duration and that the L-type calcium channel blocker nifedipine, and pinacidil (opens ATP-sensitive potassium channels and produces direct peripheral vasodilatation of the arterioles) shortened the action potential duration (Wang et al., 2014). Roden and Viswanathan (2005) described the genetics of acquired long QT syndrome including among others procedures how toanalyze the role of DNA variants in mediating individual susceptibility
Designing a Low-Cost ECG Sensor and Monitor: Practical Considerations and Measures
Published in Daniel Tze Huei Lai, Rezaul Begg, Marimuthu Palaniswami, Healthcare Sensor Networks, 2016
Ahsan H. Khandoker, Brian A. Walker
Normal heart rates are somewhere between 60 and 90 beats per minute. The PR interval is usually 180–200 ms for an adult and 150–180 ms for a child. The QRS interval is between 70 and 100 ms (Huff 2005). The QT dispersion (QTd) for purposes of diagnosis depends greatly on the heart rate and is given approximately by Bazett’s formula (Hegarty 2007). However, Bazett’s formula has proven to be inaccurate at high and low heart rates, and other formulas are often used instead. In a healthy patient, QTd is less than or equal to 400 ms (Yanowitz 2006), which sets an upper limit on the QT interval depending on the heart rate. Abnormally long QT intervals result in long QT syndrome, which could lead to ventricular fibrillation and sudden death (Mayo Foundation for Medical Education and Research 2008). One important parameter based on the QT interval is the QT interval dispersion, which is the statistical standard deviation of the QT interval. A study in Venezuela (Fuenmayor et al. 1998) has revealed that ECG signals from malnourished children had higher QT interval dispersions and also exhibited flattened or inverted T waves. Increased QT interval dispersions are also an indication of type 1 diabetes. It is clear that the QT interval is an important parameter used in diagnosis.
Implications of CRISPR Technology in Biological Systems
Published in Jyoti Ranjan Rout, Rout George Kerry, Abinash Dutta, Biotechnological Advances for Microbiology, Molecular Biology, and Nanotechnology, 2022
Kikku Sharma, Souvik Sen Gupta
Cardiovascular diseases constitute a major and increasing health problem in today’s world. There are many challenges to gain deeper knowledge about the common and less common causes of cardiovascular mortality. Genetic testing and bioinformatic analyzes have helped to identify the susceptibility of subjects to particular cardiac diseases like coronary and peripheral artery disease (CAD and PAD), rheumatic, hypertensive and congenital heart disease, cerebrovascular disease (stroke), and arrhythmias. The innovative discovery of induced pluripotent stem cells revolutionized the field of genome editing and now the iPS cells are widely used in cardiomyogenesis. iPS cells derived from cardiomyocytes (CM) are used as a unique tool in the field, wherein several scientists have made efforts toward satisfactory in vitro maturation of iPS cells to generate a better model for cardiac pathologies. The iPS cell has many potential functions. For example, if an individual is affected with long QT interval then the iPS cells from this individual may be induced to generate functional CM, which may address the problem. In the case of individuals with structural cardiac defects such as dilated cardio-myopathy (DCM) and hypertrophic cardiomyopathy (HCM), the iPS cells show mutations. The iPS cells derived from DCM show a mutation in a gene that encodes for troponin which leads to abnormality in Ca2+ handling and also abnormal arrangement of sarcomeric actin that leads to a decrease in the contractility of the heart. A single missense mutation in the MYH7 gene of the iPS cells derived from HCM patients show unorganized sarcomere and decreased electrophysiological polarity that leads to serious problems. The CRISPR-CAS9 system has been experimentally used for gene knockin and knockout in human iPS cells. So this technology may be used to correct the genetic mutations in the iPS cell model. Barth syndrome is an X-linked genetic cardiac disease that may be eradicated by the combination of iPS cells and CAS9-mediated genome editing. Mutation in the tafazzin (TAZ) gene of iPS cells of a healthy donor by CAS9-mediated genome editing tools have helped to identify the relationship between TAZ gene mutations that cause the disease and mitochondrial phenotypes. The titin gene mutations in DCM have also been evaluated by the CRISPR-CAS9 system (Motta et al., 2017). The CRISPR-CAS9 system can also edit genes of somatic cells in vivo. It can disrupt the proprotein convertase subtilisin/Kexin type 9 (PCSK9) gene, which leads to the lowering of blood cholesterol resulting in the lowering of coronary heart disease. By rectifying the mutation in the calmodulin gene of iPS cells, we can overcome the problem of long QT syndrome. Long QT-associated calmodulin inactivation occurs due to the mutation in CALM1, CALM2 and CALM 3 gene. The long QT syndrome is mediated by the mutation in six calmodulin producing alleles and CRISPR interference technology can selectively rectify these mutated alleles. In this technique, the dCas9 and its associated g RNA bind to the promoter and inactivate RNA polymerase leading to transcriptional deactivation of the mutant alleles.
Usefulness of insertable cardiac monitors for risk stratification: current indications and clinical evidence
Published in Expert Review of Medical Devices, 2023
Amira Assaf, Dominic AMJ Theuns, Michelle Michels, Jolien Roos-Hesselink, Tamas Szili-Torok, Sing-Chien Yap
Congenital long QT syndrome (LQTS) is an inherited disease characterized by a prolonged heart-rate corrected QT interval and is associated with an increased risk of malignant ventricular arrhythmias triggered by early afterdepolarizations [47]. The diagnosis is based on a high Schwartz score (≥3.5) and/or the presence of a pathogenic mutation. Pathogenic mutations are found in up to 75% of patients and mainly comprise loss-of-function variants in KCNQ1 and KCNH2, or gain-of-function variants in SCN5A [48,49]. The cornerstone of treatment are beta blockers, preferably non-selective agents (i.e. nadolol and propranolol), and lifestyle measures (i.e. avoidance of QT prolonging drugs, correction of electrolyte abnormalities, avoidance of genotype-specific triggers) [18]. The antiarrhythmic effect of beta blockers is due to the prevention of early afterdepolarizations. In addition, LQT3 patients may benefit from blockers of the late sodium inward current (mexiletine, flecainide or ranolazine) [50]. In patients in whom beta blockers are not effective, not tolerated, not accepted, or contraindicated, left cardiac sympathetic denervation is recommended [17,18].
Spectral and computational chemistry studies for the optimization of geometry of dioxomolybdenum(VI) complexes of some unsymmetrical Schiff bases as antimicrobial agent
Published in Journal of Coordination Chemistry, 2018
Mohammad Nasir Uddin, Didarul Alam Chowdhury, Nobuyuki Mase, Mohammad Fazlur Rashid, Monir Uzzaman, Amrin Ahsan, Nur Mostaq Shah
Pharmacokinetic properties are calculated in AdmetSAR which predicts all compounds are noncarcinogenic [25, 36]. Pharmacokinetic parameters were calculated to search their biological action, for example, absorption, distribution, metabolism, excretion and toxicity. Selected pharmacokinetic parameters of all ligands and complexes are given in Supplementary Material Table S7. All ligands are P-glycoprotein noninhibitors. P-glycoprotein inhibition can block the absorption, permeability and retention of the drugs. P-glycoprotein inhibition can block the absorption, permeability and retention of the ligands. The ligands show positive response for blood brain barrier (BBB) criteria, predicting that drugs will go through BBB. However, Schiff base ligands show noninhibitory property for human ether-go-go-related gene (hERG). Inhibition of hERG can lead to long QT syndrome [37].
Pharmacokinetic and toxicological prediction of the chemical constituents of the essential oil of the leaves of Croton heliotropiifolius Kunth
Published in Journal of Toxicology and Environmental Health, Part A, 2023
Rosemarie Brandim Marques, Maria Das Dores Barreto Sousa, Wesley de Sousa Santos, Neirigelson Ferreira de Barros Leite, Esdras Morais Sobreiro Lima, Angélica Lima Soares, Charllyton Luís Sena da Costa, Francisco Artur e Silva Filho, Antônio Luiz Martins Maia Filho, Evandro Paulo Soares Martins, Ricardo Martins Ramos, Antonio de Macedo Filho
Voltage-gated potassium channels of the human ether-a-go-gorelated (hERG) type are essential for normal electrical activity in the heart. Dysfunction of the hERG channel results in long QT syndrome (LQTS), characterized by delayed repolarization and prolongation of the QT interval of the cardiac cell action potential, which enhances the risk of ventricular arrhythmias and sudden death. Thus, compounds that act on this channel and that possibly initiate long QT syndrome have been eliminated early in the non-clinical development process in safety assessment (Sanguinetti and Tistani-Firouzi 2006; Yu, Ijzerman, and Heitman 2015).