Recent Advances in Lentiviral Vector Development and Applications

Abstract

Lentiviral vectors (LVs) have emerged as potent and versatile vectors for ex vivo or in vivo gene transfer into dividing and nondividing cells. Robust phenotypic correction of diseases in mouse models has been achieved paving the way toward the first clinical trials. LVs can deliver genes ex vivo into bona fide stem cells, particularly hematopoietic stem cells, allowing for stable transgene expression upon hematopoietic reconstitution. They are also useful to generate induced pluripotent stem cells. LVs can be pseudotyped with distinct viral envelopes that influence vector tropism and transduction efficiency. Targetable LVs can be generated by incorporating specific ligands or antibodies into the vector envelope. Immune responses toward the transgene products and transduced cells can be repressed using microRNA-regulated vectors. Though there are safety concerns regarding insertional mutagenesis, their integration profile seems more favorable than that of gamma-retroviral vectors (gamma-RVs). Moreover, it is possible to minimize this risk by modifying the vector design or by employing integration-deficient LVs. In conjunction with zinc-finger nuclease technology, LVs allow for site-specific gene correction or addition in predefined chromosomal loci. These recent advances underscore the improved safety and efficacy of LVs with important implications for clinical trials.

MSP58 Knockdown Inhibits the Proliferation of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo

“…The lentiviral vectors for shRNA expression were used in our system. This approach allows for the stable suppression of target gene expression both in cell culture conditions and in animals (Sumimoto et al, 2007;Bos et al, 2009;Chumakov et al, 2010;Matrai et al, 2010).…”

Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE

“…23,24 In order to minimize such risks, novel integrative vectors, which show increased safety, have been developed and some of them have already been used in clinical trials. 25 Two main strategies are currently under investigation to minimize potential risks and increase the biosafety profile of vectors. One is the use of lentiviral instead of g-retroviral vectors, as they were shown to be less prone to integrate near oncogenes and near their origin of transcription.…”

Advances in Gene Delivery Systems

“…[20,21] Lentiviruses favour transgene integration near active transcription sites, while oncoretroviruses preferentially integrate at the transcription start site. [11,22] Without any accessory genes, current lentiviral vectors are considered reasonably safe, because the replication of the vectors is highly inhibited and the possibility of recombination is reduced. [22,23] Recent work showed successful gene transfer by lentiviral vectors into quiescent T and B lymphocytes for immunotherapy of several genetic dysfunctions of the haematopoietic system.…”

“…[11,22] Without any accessory genes, current lentiviral vectors are considered reasonably safe, because the replication of the vectors is highly inhibited and the possibility of recombination is reduced. [22,23] Recent work showed successful gene transfer by lentiviral vectors into quiescent T and B lymphocytes for immunotherapy of several genetic dysfunctions of the haematopoietic system. [24][25][26][27] Results from an ongoing lentivirus-based gene therapy trial in France for β-thalassaemia showed that one patient had not required blood transfusions for the past 16 months.…”