Targeted Gene Therapy Via Lentiviral Vectors

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Introduction

By Drew Albrecht
Gene therapy is a revolutionary technique that is on the forefront of medical innovation. With the use of targeted gene therapy, disease-specific treatments can be made to cure people of diseases that were once thought to be incurable. There are many methods that are being tested right now to advance gene therapy, but one that is gaining serious traction are lentiviral vectors. Vectors based on viruses are very attractive for gene therapy because viruses are naturally very good at getting into cells. Lentiviruses are even better because they insert their genes into the host’s genomes. With the creation of lentiviral particles with a specific gene of interest, researchers can target affected cells and recover the corrected DNA. This methodology is already being used to treat and cure many diseases today, and the future holds many promises for beating the unbeatable.

Gene Therapy Overview

Figure 1. Schematic drawing of ex vivo and in vivo gene therapy Bulcha et al. (2021)

Genetic disorders like cystic fibrosis, phenylketonuria, sickle-cell anemia, and many more, are a result of mutated or absent genes. The goal of gene therapy is to treat or cure such diseases via genetic modification of the cells in an affected individual. Genetic modification can rewire the cells to either produce a therapeutic effect or simply just replace the mutated or missing DNA. Gene therapy can either be ex vivo, where genetic modification of cells occurs outside of the body followed by their transplantation back into the body[Gowing] or in vivo, when genetic information is directly inserted into the body via a vector[Mendell]. Vectors are molecules that aid in the transportation of genetic information all over the body. While both methods prove useful for fighting diseases with genetic modification, in vivo is the more appropriate method for a targeted approach. Performing in vivo gene therapy, there are two different types of vectors: nonviral and viral. Non-viral vectors can be naked DNA, particle based, or chemical based, all transporting DNA throughout the body without the use of a virus. Like the name suggests, viral vectors use the natural tendencies of viruses to infect a host by inserting its DNA into the cytoplasm. Viruses are the perfect carrier to deliver DNA to a target because that is what they do naturally. While non-viral are overall less effective, they are still a promising option due to the low cost, reduced pathogenicity, and ease of production. However, there are a few types of viral vectors that are being tested to drastically change the face of medicine in disease treatment. Currently, the three types of viruses that are being used are adenoviruses (AVs), and adeno-associated viruses (AAVs), and retroviruses, also called lentiviruses.

Viral Vectors

Lentiviruses

Lentivirus Infection Pathway

Figure ?. Infection Pathway of HIV-1 Lentivirus. Perilla et al. (2022)

Lentiviral Vectors

Figure ?. Simplified schematic of the HIV-1 structure and respective proteins. Rittiner et al. (2020)

How Do Lentivirus Vectors Work

Figure ?. The core plasmids and transfer plasmid that are packaged into a lentiviral particle. Milone and O'Doherty (2018)

Figure ?. Functions of known lentivirus proteins. Genemedi

HIV As a Viral Vector

Using HIV To Fight HIV

Figure ?. Timothy Ray Brown, one of the only cured survivors of HIV/AIDS. NIH

Current Treatments

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