Abstract
Viruses have been repurposed into tools for gene delivery by transforming them into viral vectors. The most frequently used vectors are lentiviral vectors (LVs), derived from the human immune deficiency virus allowing efficient gene transfer in mammalian cells. They represent one of the safest and most efficient treatments for monogenic diseases affecting the hematopoietic system. LVs are modified with different viral envelopes (pseudotyping) to alter and improve their tropism for different primary cell types. The vesicular stomatitis virus glycoprotein (VSV-G) is commonly used for pseudotyping as it enhances gene transfer into multiple hematopoietic cell types. However, VSV-G pseudotyped LVs are not able to confer efficient transduction in quiescent blood cells, such as hematopoietic stem cells (HSC), B and T cells. To solve this problem, VSV-G can be exchanged for other heterologous viral envelopes glycoproteins, such as those from the Measles virus, Baboon endogenous retrovirus, Cocal virus, Nipah virus or Sendai virus. Here, we provide an overview of how these LV pseudotypes improved transduction efficiency of HSC, B, T and natural killer (NK) cells, underlined by multiple in vitro and in vivo studies demonstrating how pseudotyped LVs deliver therapeutic genes or gene editing tools to treat different genetic diseases and efficiently generate CAR T cells for cancer treatment.
Highlights
Viral vectors have been derived from a large number of viruses, which were transformed into efficient tools for delivery of genes into cells of interest, thanks to their unique characteristics.Viruses have undergone modifications in their replication pathway to reduce risks when used for therapeutic purposes
In recent years the number of clinical trials in which they are employed has been reduced to a 0.5% in contrast to 11 years ago when murine leukemia virus (MLV)-derived vectors accounted for 21%
One of the drawbacks of baboon envelope (BaEV)-lentiviral vectors (LVs) and H/F-LVs is that their infectious titers are lower than their vesicular stomatitis virus glycoprotein (VSV-G) LV counterparts, which is a hurdle that needs to be overcome for future clinical applications
Summary
Viral vectors have been derived from a large number of viruses, which were transformed into efficient tools for delivery of genes into cells of interest, thanks to their unique characteristics. Genotoxicity, one of the most problematic events caused by integration of the vector sequences into the host cell genome, can result in malignant cell transformation This is called insertional mutagenesis—disruption or upregulation of genes due to the viral integration event—and causes outgrowth of clones in a polyclonal population [6]. This was the case for different gene therapy clinical trials using gamma retroviral vectors such as X-linked severe combined immunodeficiency (SCID-X1) [13,14], CGD [15] and Wiskott–Aldrich syndrome (WAS) [16]. The solution is to exchange the HIV envelope glycoprotein for heterologous glycoproteins on the LV surface, a process called pseudotyping [4]
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