Gene therapy was conceived during the early and mid part of the 20th century. At first, it was considered a revolutionary biomedical procedure, which could potentially cure any disease for which the molecular bases were understood. Since then, gene therapy has gone through many stages and has evolved from a nearly unrealistic perspective to a real life application. Clinical efficacy in humans was demonstrated at the beginning of this century after its successful application in small-scale clinical trials to cure severe immunodeficiency in children. However, their successes were overshadowed some time later by the occurrence of vector-related leukaemia in a number of treated children. It is in this context that lentiviral vectors have appeared, with improved efficiency and, possibly, increased biosafety. Very recently, the first clinical trials with lentivectors have been carried out with some success.
This Brief firstly defines gene therapy, and places lentivectors within this fascinating therapeutic strategy. Then follows a comprehensive description of the development of retroviral and lentiviral vectors and how to specifically target distinct cell types and tissues. The authors also discuss the application of lentivector gene therapy for the treatment of cancer and autoimmune diseases, ending with the application of lentivectors in human gene therapy clinical trials.
Mục lục
1 Introduction to gene therapy.- 1.1 The concept of gene therapy.- 1.2 Origins of gene therapy.- 1.3 Gene therapy in the 1970s.- 1.4 Gene therapy in the 1980s.- 1.5 The breakthroughs in gene therapy from the 1990s and 2000s.- 1.6 Current human gene therapy and lentiviral vectors.- 1.7. Concluding remarks.- 2 Development of retroviral and lentiviral vectors.- 2.1 Retrovirus biology.- 2.2 Vectors based on γ -retroviruses.- 2.3 Vectors based on lentiviruses.- 2.4 Summary and conclusions.- 3 Cell and tissue gene targeting with lentiviral vectors.- 3.1 Introduction.- 3.2 Modification of lentivector tropism by pseudotyping (surface targeting).- 3.3 Transcriptional targeting.- 3.4 Post-transcriptional targeting.- 3.5 Conclusions.- 4 Immunomodulation by genetic modification using lentiviral vectors.- 4.1 Introduction to genetic immunotherapy.- 4.2 Lentivector gene therapy for immunization.- 4.3 Lentivector gene therapy for the treatment of autoimmune disease.- 4.4 Conclusions.- 5 Clinical grade lentiviral vectors.- 5.1 Introduction.- 5.2 Good manufacturing practise guidelines and clinical grade vector preparations.- 5.3 Scaling-up lentivector production for clinical application.- 5.4 Purity of clinical grade lentivectors.- 5.5 Biosafety.- 5.6 Final considerations and conclusions.- 6 Human gene therapy with retrovirus and lentivirus vectors.- 6.1 Introduction.- 6.2 Correction of Severe Combined Immunodeficiency-X1.- 6.3 Correction of X-linked chronic granulomatous disease.- 6.4 Correction of X-linked adrenoleukodystrophy.- 6.5 Correction of b-thalassaemia.- 6.6 Correction of Wiscott-Aldrich syndrome.- 6.7 Conclusions and final considerations.
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