Is genetic engineering the holy grail to cure infectious diseases?

Employing genetic engineering for the treatment of infectious diseases means introducing specific genes that discretely inhibit or block the functions of target genes.

The advent of genetic engineering in recent times has shrunk the time needed to evolve any species or organism. It is an excellent amalgamation of science and the ecosystem’s natural process to meet the population’s needs. The advantages of genetic engineering are numerous, including the production of genetically modified crops and seeds, medicinal foods that can be used as vaccines, increasing the food supply, modifying organisms to exhibit traits of interest; and genetic engineering has come a long way.

The occurrence of infectious diseases has been escalating worldwide. With approximately 37.7 million people affected by HIV by 2020, 10.6 million people affected by Tuberculosis by 2021, and almost 3-5 million people/year afflicted by Influenza, it is a matter of acute concern. With the success of genetic engineering in other domains, attention is being channeled to using this technology to combat or cure infectious diseases.

“The advance of genetic engineering makes it quite conceivable that we will begin to design our evolutionary progress”- Isaac Asimov

Employing genetic engineering for the treatment of infectious diseases means introducing specific genes that discretely inhibit or block the functions of target genes of interest or impede certain gene products. The main aim of the entire process is to restrict the replication of infectious organisms (viruses, bacteria).

The success of gene therapy to treat infectious diseases depend upon several factors, such as recruiting pertinent target cell/ tissue, the efficiency of the vector to transfer the gene of interest to the targeted region, the required expression rate of the gene, and the production of sufficient gene products. The operation of genetic engineering to treat infectious diseases can be classified into three mainstream groups:

  1. Gene therapies based on nucleic acids, including DNA, RNA, and ribozymes

Antisense (nucleic acids complementary to the mRNA of specific genes) nucleic acid transcripts can be formulated to specifically target various regions of the genome of the infectious organism. The antisense nucleotides are degraded by nucleases which inhibit their translation into mRNA and thus result in no functional protein production. 

  • A benefit of antisense RNA to be used for inhibitory purposes of target genes is its lack of immunogenicity which means that they do not generate any immune reaction in the body.

Ribozymes are antisense RNA molecules that play their role in the process of gene therapy by binding to the target gene/molecule of interest, cleaving the bond at the target site, and thus preventing any replication of the division of the nucleic acid. 

  • One of the advantages of utilizing tailored RNA is that they are not used up in the process, so it can be used multiple times to achieve the desired effect. Moreover, ribozymes can be produced from small transcriptional units, and thus, they can be produced in large quantities targeting multiple genomic regions of the infectious agent via a single vector construct. Their catalytic property allows them to be excellent gene expression inhibitors at low concentrations, thus making them a significant candidate for genetic engineering.
  1. Immunotherapeutic approaches such as genetic vaccines

One of the ways to prevent the body against infectious disease is to expose the protein components of the infectious agent to the body’s immune system, thereby eliciting an immune response in the body. Such as immune response will allow the body to fight the infection and reduce the severity of the disease by allowing the immune system to combat the infection.

A prominent example is DNA-based vaccines, which are developed by transferring DNA plasmid into target cells by genetically engineering the DNA.

  1. Gene therapies based on the alteration of protein moieties, such as single-chain antibodies

There are three primary protein moieties: anti-infectious cellular proteins and trans-dominant harmful proteins.

  • Anti-infectious cellular proteins are those recruited from normal cellular genes exhibiting specific inhibitory activities. The inhibitory action of these proteins can enable their binding to the infectious agent and directly/indirectly inhibit cellular components of the infectious agent, thus inhibiting viral gene expression.
  • Trans-dominant Negative Proteins (TNPs) are mutants of the structural or regulatory proteins that demonstrate negative phenotype, a trait that can inhibit the replication of infectious agents. However, a critical issue with these moieties is that when genetically altered/engineered, they may activate the body’s immune system, resulting in self-destruction. Such an occurrence ultimately reduces the efficacy of antiviral gene therapy and defeats its purpose of curing infectious diseases.
  • Single Chain Antibodies, or intrabodies, are single-chain, intracellularly expressed antibodies. They can directly bind to the gene of interest, interact with them and inhibit gene function, thereby deranging the life cycle of the infectious agent and preventing its replication and proliferation. 

CRISPR: A revolutionary tool

Else known as Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR/CAS 9 is a groundbreaking genetic editing tool that plays a significant role in infectious disease research. An array of various infectious diseases can be treated with CRISPR, including viruses, fungi, and bacteria.

  • How does CRISPR/CAS-9 work?

CRISPR/CAS works in three steps to prevent repeated viral attacks on bacteria.

  1. Adaptation

The invading virus inserts its small DNA fragments into the CRISPR sequence as new spacer molecules.

  1. CRISPR RNA production

CRISPR repeats and spaces residing in bacterial DNA undergo transcription producing a single-chain RNA molecule. CRISPR RNA cuts this newly formed RNA into shorter pieces.

  1. Targeting 

CRISPR RNA channels the molecular machinery of the bacterial host cell to destroy the viral components.

Human Immunodeficiency Virus (HIV) is an RNA virus that integrates its genetic material into host genomes. CRISPR can be used to specifically target and remove the DNA from the host cell genome. A high-resolution CRISPR screen in human CD4+ T cells was developed by Dr. Nevan Krogan’s lab in 2018 that identifies factors involved in HIV infection.

Fungal infections threaten the human population contributing to a total of 1.6 million deaths per year worldwide. CRISPR has allowed the creation of new approaches to manipulate and modify fungi genetically, the treatments for which are a challenge. For instance, CRISPR mutagenesis was developed in the fungus Aspergillus fumigatus.

CRISPR diagnostic tools for SARS-CoV-2, an RNA virus, have proven to be an efficacious treatment for the virus by yielding accurate results, producing faster results than PCR tests. Cardea Bio is a company involved in using CRISPR diagnostic elements for pathogen and infectious disease testing.

Monitoring, evaluating, and finding therapeutic approaches to combat the spread of infectious diseases is a dire need. Genetic engineering can be exploited to manipulate these infectious agents, thus preventing or reducing their replication to inhibit their spread. Though the focus is driven by integrating technology to combat infectious diseases, there is an excellent arena of untapped research.

“With genetic engineering, we will be able to increase the complexity of our DNA and improve the human race. But it will be a slow process because one will have to wait about 18 years to see the effect of changes to the genetic code”- Stephan Hawking