RNA interference(RNAi)is an ancient biological mechanism used to defend against external invasion.It theoretically can silence any disease-related genes in a sequence-specific manner,making small interfering RNA(siRNA...RNA interference(RNAi)is an ancient biological mechanism used to defend against external invasion.It theoretically can silence any disease-related genes in a sequence-specific manner,making small interfering RNA(siRNA)a promising therapeutic modality.After a two-decade journey from its discovery,two approvals of siRNA therapeutics,ONPATTRO®(patisiran)and GIVLAARI™(givosiran),have been achieved by Alnylam Pharmaceuticals.Reviewing the long-term pharmaceutical history of human beings,siRNA therapy currently has set up an extraordinary milestone,as it has already changed and will continue to change the treatment and management of human diseases.It can be administered quarterly,even twice-yearly,to achieve therapeutic effects,which is not the case for small molecules and antibodies.The drug development process was extremely hard,aiming to surmount complex obstacles,such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity,stability,specificity and potential off-target effects.In this review,the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed.All clinically explored and commercialized siRNA delivery platforms,including the GalNAc(N-acetylgalactosamine)–siRNA conjugate,and their fundamental design principles are thoroughly discussed.The latest progress in siRNA therapeutic development is also summarized.This review provides a comprehensive view and roadmap for general readers working in the field.展开更多
Throughout its 40-year history,the field of gene therapy has been marked by many transitions.It has seen great strides in combating human disease,has given hope to patients and families with limited treatment options,...Throughout its 40-year history,the field of gene therapy has been marked by many transitions.It has seen great strides in combating human disease,has given hope to patients and families with limited treatment options,but has also been subject to many setbacks.Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and,even in rare cases,death.At the heart of this dichotomous field are the viral-based vectors,the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms,and have radically changed the face of medicine.Within the past 5 years,the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes,these modalities range from vector-based cancer therapies,to treating monogenic diseases with life-altering outcomes.At present,the three key vector strategies are based on adenoviruses,adeno-associated viruses,and lentiviruses.They have led the way in preclinical and clinical successes in the past two decades.However,despite these successes,many challenges still limit these approaches from attaining their full potential.To review the viral vector-based gene therapy landscape,we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.展开更多
Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for soli...Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.展开更多
基金supported by the National Natural Science Foundation of China(31871003,31901053)the Hunan Provincial Natural Science Foundation of China(2018JJ1019,2019JJ50196)+3 种基金the Hu-Xiang Young Talent Program(2018RS3094)the Fundamental Research Funds for the Central Universities(3052018065)the Beijing Institute of Technology Research Fund Program for Young Scholars.It was also supported,in part,by grants from the National Science and Technology Major Project of China(2019ZX09301-132)Program for Changjiang Scholars and Innovative Research Team in University of China(IRT_15R13).
文摘RNA interference(RNAi)is an ancient biological mechanism used to defend against external invasion.It theoretically can silence any disease-related genes in a sequence-specific manner,making small interfering RNA(siRNA)a promising therapeutic modality.After a two-decade journey from its discovery,two approvals of siRNA therapeutics,ONPATTRO®(patisiran)and GIVLAARI™(givosiran),have been achieved by Alnylam Pharmaceuticals.Reviewing the long-term pharmaceutical history of human beings,siRNA therapy currently has set up an extraordinary milestone,as it has already changed and will continue to change the treatment and management of human diseases.It can be administered quarterly,even twice-yearly,to achieve therapeutic effects,which is not the case for small molecules and antibodies.The drug development process was extremely hard,aiming to surmount complex obstacles,such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity,stability,specificity and potential off-target effects.In this review,the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed.All clinically explored and commercialized siRNA delivery platforms,including the GalNAc(N-acetylgalactosamine)–siRNA conjugate,and their fundamental design principles are thoroughly discussed.The latest progress in siRNA therapeutic development is also summarized.This review provides a comprehensive view and roadmap for general readers working in the field.
基金supported by grants from the University of Massachusetts Medical School(an internal grant)and by the National Institutes of Health(R01NS076991-01,1P01All00263-01,4P01HL131471-02,UG3 HL147367-01,1U19AI149646,and R01HL097088).
文摘Throughout its 40-year history,the field of gene therapy has been marked by many transitions.It has seen great strides in combating human disease,has given hope to patients and families with limited treatment options,but has also been subject to many setbacks.Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and,even in rare cases,death.At the heart of this dichotomous field are the viral-based vectors,the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms,and have radically changed the face of medicine.Within the past 5 years,the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes,these modalities range from vector-based cancer therapies,to treating monogenic diseases with life-altering outcomes.At present,the three key vector strategies are based on adenoviruses,adeno-associated viruses,and lentiviruses.They have led the way in preclinical and clinical successes in the past two decades.However,despite these successes,many challenges still limit these approaches from attaining their full potential.To review the viral vector-based gene therapy landscape,we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.
基金This work was supported by grants from the National Key R&D Program of China(2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)+2 种基金the National Natural Science Foundation of China(81821002,82130082,81790251,81972665,82173003,82102738 and 82103168)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD22007 and ZYJC21004)the Science and Technology Foundation of Shenzhen(JCYJ20200109113810154).BioRender was used to create the figures.
文摘Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.
