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A new generation of lentivirus for gene therapy

Using NMR spectroscopy to detect cell morphology alterations in vivo

Researchers from Innovative Therapies Unit (STI/Service des Thérapies Innovantes) have developed a new generation of lentivirus, paving the way for the use of Mauritian cynomolgus macaque as a pre-clinical study model for the development of new gene therapy products.

Published on 22 July 2019

Recent marketing approval for genetically engineered hematopoietic stem and T cells bears witness to the substantial improvements in lentiviral vectors over the last two decades, but evaluations of the long-term efficacy and toxicity of gene and cell therapy products will, nevertheless, require further studies in nonhuman primate models.

Macaca fascicularis monkeys from Mauritius have a low genetic diversity and are particularly useful for reproducible drug testing. In particular, they have a genetically homogeneous class I major histocompatibility complex system that probably mitigates the variability of the response to simian immunodeficiency virus infection. However, the transduction of simian cells with human immunodeficiency virus type 1 (HIV-1)-derived vectors is inefficient due to capsid-specific restriction factors, such as the tripartite motif-containng protein tripartite motif 5α, which prevent infection with non-hostadapted retroviruses.

Researchers from STI have developed y a new modified capsid of the macaque-trophic HIV-1 clone MN4/ LSQD into the packaging system and compared transduction efficiencies between hematopoietic cells transduced with this construct and cells transduced with HIV-1 NL4-3-derived packaging constructs.

Capsid modification increased transduction efficiency in all hematopoietic cells tested (by factors of up to 10), including hematopoietic progenitor cells, repopulating cells, and T cells from Mauritian Macaca fascicularis, regardless of vector structure or purification method.

This study also established culture conditions similar to those used in clinical practice for the efficient transduction of hematopoietic stem and progenitor CD34+ cells.

These results suggest that the procedure is suitable for use in Mauritian Macaca fascicularis, which can therefore be used as a model in preclinical studies for hematopoietic gene and cell therapy.

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