Подготовка у универсиаде 2012 / Lentiviral vectors basic to translational

Lentiviral vectors in the clinic

The first Phase I clinical trial using a HIV-based lentiviral vector expressing an antisense gene against HIV env was started for AIDS gene therapy in 2003 [230]. In that study, a VSV-G-pseudotyped vector with no HIV-1 accessory proteins, named VRX496, was produced from an advanced two-plasmid packaging system [231]. Five subjects who received a single dose ( 1010 cells) of VRX496-transduced autologous CD4+ T- cells resulted in an increase of CD4+ T-cells (four out of five subjects) and decrease of viral load (five out of five participants) after 1 year [232]. Lentiviral vector-mediated gene therapy for haematopoietic stem cells has also demonstrated initial clinical benefits in X-linked adrenoleukodystrophy [233]. A Phase I/II clinical trial of β-globin gene therapy for β-thalassaemia also began in 2007 [234]. A self-inactivating lentivector, LentiGlobin, contains large elements of the β-globin locus control region, and chromatin insulators (cHS4) were used to transduce CD34+ cells [235]. After approximately 3 years of treatment, the patients have corrected β-globin gene and stable blood haemoglobin levels [235]. No insertional mutagenesis has been reported from both trials so far, and these studies provide therapeutic benefit for the patients.

CLOSING REMARKS

As summarized above, considerable efforts have been made to increase the safety and efficacy of lentiviral vector systems. Currently available vectors are mostly generated from multiple plasmids, with no HIV-1 accessory gene and with self-inactivating modification, yet show high gene transduction efficiency in vitro and in vivo. It is also notable that no RCL has been observed in third-generation HIV-1 vectors. Because of their increased safety and proven efficiency, we can now purchase ready-to- use lentivector particles from various vendors. It is likely that lentivector technology will evolve further and expand into new research fields where the vector users may have a limited background in lentiviruses.

This state-of-the-art system represents a huge success for lentiviruses as a gene transfer vector system. However, it should be noted that these vectors are derived from pathogenic viruses. The possibility of generating an RCL may be very low, but may not be zero, where a single infection event of an oncogene-carrying lentiviral vector may be enough to induce tumours. (For guidance on biosafety considerations for research with lentiviral vectors, see http://oba.od.nih.gov/oba/ rac/Guidance/LentiVirus_Containment/pdf/Lenti_Containment_ Guidance.pdf.) When sufficient precautions are taken, the lentiviral vector technology will provide an effective and versatile platform which achieves various creative and innovative applications.

ACKNOWLEDGEMENT

We thank Chisato Sakuma (CINE-BOY) for creating custom three-dimensional animations.

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