Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

被引:79
作者
Baruteau, Julien [1 ,2 ,3 ]
Waddington, Simon N. [3 ,4 ]
Alexander, Ian E. [5 ,6 ,7 ]
Gissen, Paul [1 ,2 ,8 ]
机构
[1] UCL, Great Ormond St Inst Child Hlth, Genet & Genom Med Programme, London, England
[2] Great Ormond St Hosp Children NHS Fdn Trust, Metab Med Dept, London, England
[3] UCL, Inst Womens Hlth, Gene Transfer Technol Grp, London, England
[4] Univ Witwatersrand, Wits SAMRC Antiviral Gene Therapy Res Unit, Fac Hlth Sci, Johannesburg, South Africa
[5] Childrens Hosp Westmead, Gene Therapy Res Unit, Westmead, NSW, Australia
[6] Childrens Med Res Inst, Westmead, NSW, Australia
[7] Univ Sydney, Discipline Child & Adolescent Hlth, Sydney, NSW, Australia
[8] UCL, MRC Lab Mol Cell Biol, London, England
基金
英国医学研究理事会;
关键词
DEPENDENT ADENOVIRAL VECTORS; ADENOASSOCIATED VIRUS AAV; COAGULATION-FACTOR-IX; CANINE HEMOPHILIA-B; T-CELL RESPONSES; ORNITHINE TRANSCARBAMYLASE DEFICIENCY; INNATE IMMUNE-RESPONSE; FACTOR-VIII EXPRESSION; LONG-TERM CORRECTION; VIRAL VECTORS;
D O I
10.1007/s10545-017-0053-3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.
引用
收藏
页码:497 / 517
页数:21
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