Lyssavirus
Viral pseudotyping is a strategy that can be used to create viral vectors with new tropism and trafficking properties. Lentiviral vectors pseudotyping with lyssavirus have shown great potential in gene therapy, due to their ability to transduce neurons, offering a gene therapeutic approach for the treatment of motor neuron diseases.
Background of Lyssavirus
The Lyssavirus genus belongs to the Rhabdoviridae family and includes classical rabies virus (RV) and rabies-related viruses, such as the Mokola virus (MK), which differ with respect to phylogeny, pathogenicity, and immunogenicity. Lyssaviruses are able to infect various cell types, but tropism is primarily restricted to neurons in vivo. They interact with ubiquitous components of plasma membranes in a similar manner to the vesicular stomatitis virus (VSV), which is another member of the Rhabdoviridae family. In addition, lyssaviruses recognize specific receptors on the surface of neurons and enter neurons through these receptors. The receptors for lyssaviruses include the nicotinic acetylcholine receptor (nAChR), the neural cell adhesion molecule (NCAM), and the p75 neurotrophin receptor (NTR). They are type I transmembrane glycoproteins with an average size of 520 amino acids, which form trimers protruding from the virion surface.
The Pseudotyping of Lentiviral Vectors with Lyssavirus
Gene therapy for neurological diseases requires the transfer of genetic material to post-mitotic neurons. Primate and non-primate lentiviral vectors (LVs) are ideal candidates for this gene delivery tool because they can transduce both dividing and non-dividing cells, resulting in stable integration and long-term expression of the transgene. Targeting such vectors to specific cell populations in vivo can be achieved by pseudotyping. Since LVs have the ability to integrate into the non-dividing cell genome, including central nervous system (CNS) cells, it is tempting to increase the tropism of LVs for neurons by producing pseudotypes with the glycoproteins (GPs) of viruses that exhibit a powerful neurotropism.
LVs such as those derived from the human immunodeficiency virus (HIV), feline immunodeficiency virus (FIV), and equine infectious anemia virus (EIAV) have been pseudotyped with RV glycoprotein (RVG) and MK glycoprotein (MKG). The lyssavirus GPs used to pseudotype LVs are mainly derived from the RV strain RabSADB19 and the MK MokETH strain. This pseudotyping extends the host range of LVs to various cell types, especially neuronal cells. What's more, pseudotyped LVs can effectively deliver genes to neurons and mediate stable and long-term transduction of neural cells.
Application of LVs Pseudotyped with Lyssavirus GPs
The pseudotyped LVs with lyssavirus GPs have potential clinical importance in the treatment of motor neuron disease. For instance, intramuscular injection of EIAV vectors pseudotyped with RVG results in transgene expression in spinal motor neurons. In an animal model of familial amyotrophic lateral sclerosis (ALS), EIAV-based vectors encoding vascular endothelial growth factor (VEGF) and pseudotyped with the RVG extend the lifespan of animals by 30%. In addition, EAIV vectors expressing human survival motor neuron (SMN) cDNA and pseudotyped with RVG restore SMN protein levels in motor neurons and reduce motor neuron death. These examples demonstrate that LVs pseudotyped with GPs derived from Lyssavirus (RV and rabies-related virus) represent a considerable possibility of targeting gene therapy for neurodegenerative diseases specifically to neuronal cells.
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