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Joost Groot Yizhou Zhou Eric Marshall Patrick Cullen Thomas Carlile Dongdong Lin Chong-Feng Xu Justin Crisafulli Chao Sun Fergal Casey Baohong Zhang Christina Alves 《Biotechnology journal》2021,16(8):2000548
In recent years, High-Throughput Sequencing (HTS) based methods to detect mutations in biotherapeutic transgene products have become a key quality step deployed during the development of manufacturing cell line clones. Previously we reported on a higher throughput, rapid mutation detection method based on amplicon sequencing (targeting transgene RNA) and detailed its implementation to facilitate cell line clone selection. By gaining experience with our assay in a diverse set of cell line development programs, we improved the computational analysis as well as experimental protocols. Here we report on these improvements as well as on a comprehensive benchmarking of our assay. We evaluated assay performance by mixing amplicon samples of a verified mutated antibody clone with a non-mutated antibody clone to generate spike-in mutations from ∼60% down to ∼0.3% frequencies. We subsequently tested the effect of 16 different sample and HTS library preparation protocols on the assay's ability to quantify mutations and on the occurrence of false-positive background error mutations (artifacts). Our evaluation confirmed assay robustness, established a high confidence limit of detection of ∼0.6%, and identified protocols that reduce error levels thereby significantly reducing a source of false positives that bottlenecked the identification of low-level true mutations. 相似文献
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Tarah A. Word Ann P. Quick Christina Y. Miyake Mayra K. Shak Xiaolu Pan Jean J. Kim Hugh D. Allen Martha Sibrian-Vazquez Robert M. Strongin Andrew P. Landstrom Xander H. T. Wehrens 《Journal of cellular and molecular medicine》2021,25(13):6115-6124
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca2+) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca2+ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca2+ handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the StemdiffTM kit. Confocal Ca2+ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca2+ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC50 = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca2+ handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca2+ handling and suppresses arrhythmogenic activity in iPSC-CMs derived from a CPVT patient. Hence, this study confirms that this RyR2-inhibitor represents a promising therapeutic candidate for treatment of CPVT. 相似文献
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Paraskevi Tsingeli Maria Christina Papadatou Despoina Psillaki Vasileios Tragoulias Nikolaos Groumas Yannis Dionyssiotis 《Journal of musculoskeletal & neuronal interactions》2021,21(2):326
Von Hippel Lindau (VHL) is a hereditary multiple neoplasia syndrome. We report a case series of two siblings with Von Hippel Lindau (VHL) disease admitted to the rehabilitation department after surgical excision of Central Nervous System (CNS) haemangioblastomas. These clinical cases present rehabilitation challenges in VHL disease. We present a 39-year-old brother and his 45-year-old sister, with the diagnosis of incomplete spinal cord injury (SCI) associated with VHL syndrome lesions. The female patient was diagnosed with chronic motor incomplete cervical SCI and the male patient with acute motor incomplete thoracic SCI. Our target was to increase their functionality and improve their quality of life. Both underwent a comprehensive inpatient rehabilitation program. Programs were individualized as the female patient was admitted 15 years after her spinal cord surgical intervention, while the male patient’s admission was after 4 months of his surgery. 相似文献