Expanding the Genetic Code for Suppression of Premature Termination Codons to Alleviate Human Nonsense Mutation Diseases
作者单位：State Key Laboratory of Natural and Biomimetic DrugsDepartment of Chemical BiologySchool of Pharmaceutical SciencesPeking University
会议名称：《第十一届全国化学生物学学术会议》
会议日期：2019年
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
关 键 词：nonsense mutation premature termination codons PylRS-tRNAPyl system Duchenne muscular dystrophy Nε-2-azidoethyloxycarbonyl-L-lysine(NAEK)
摘 要：Nonsense mutations with premature termination codons(PTCs) account for approximately 11% of reported monogenic *** therapies for monogenic diseases may induce functionally compromised *** through PTCs by unnatural amino acid(UAA) incorporation systems could facilitate the full-length protein expression with minimal losses of function,which represents a promising therapeutic approach for nonsense mutation ***,we engineered a pyrrolysyl tRNA synthetase-tRNA (PylRS-tRNA ) system and investigated its potential to treat nonsense mutation in dystrophin gene,which could cause Duchenne muscular dystrophy(DMD).By using PylRS-tRNA system,we partially restored dystrophin expression in cultured myoblasts derived from a mdx mouse(DMD mouse model) and a DMD *** investigate the therapeutic potential of this system in vivo,we further generated the trans/mdx mice by crossing the PylRS-tRNAPyl UUA transgenic mice with mdx ***,administration of Nε-2-azidoethyloxycarbonyl-L-lysine(NAEK) restored the endogenous dystrophin expression up to 41% in trans/mdx mice and functioned at least 8 weeks,and muscle performance was also partially enhanced relative to mdx *** together,our results demonstrated the feasibility of the UAA incorporation systems to restore the endogenous protein expression and provided a novel therapeutic strategy for human monogenic nonsense mutation diseases.