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Gene therapy: meet the medicine of the future

Sep 20, 2021
Demi Powell
Core Spirit member since Sep 4, 2019
Reading time 5 min.

In the XX century, medicine and pharmacy made an incredible leap. A wide variety of medicines were created and put into widespread practice — from antibiotics to the first therapeutic antibodies — thanks to which the health and well-being of many people significantly improved, as well as the average life expectancy increased. However, progress cannot be stopped: the delivery of the necessary genes directly into the cells and tissues of the body or their directed editing allows you to "fix" faulty molecular processes, which gives fundamentally new opportunities for the treatment of previously incurable diseases in comparison with traditional pharmaceuticals. And since technologies do not stand still, in the future, gene therapy will take an important place in the arsenal of doctors.
In this article, we will focus specifically on gene therapy, analyze how it differs (and how it is similar) to cell therapy, consider the technologies used, go through the currently existing drugs, and also touch on the future prospects and existing limitations of such treatment.

The principle of operation: how gene therapy works

To begin with, let's understand the terminology, and for this we will consider the definition of gene therapy introduced by one of the world's main regulators of the pharmaceutical field — the US Food and Drug Administration (FDA).
So, according to the FDA, GENE THERAPY is a medical intervention based on the modification of the genetic material of living cells. The cells can be modified ex vivo for subsequent administration to humans or modified in vivo directly in the body.

How does it work?

To begin with, it is worth saying that gene therapy today consists mainly in transferring certain genes to human somatic cells, since changing the genome of germ line cells for therapeutic or other purposes is prohibited in most countries with appropriate technologies. Therefore, changes in genetic information during such treatment are not inherited and affect mainly only certain target cells in the body.

Gene therapy is also classified depending on whether changes are made to cells directly in the body or outside it.
In vivo gene therapy involves the introduction of genetic material directly by infusion; in this case, a solution containing a certain number of necessary genes, usually enclosed in carriers (or vectors — more about them below), is injected into the human body. After that, the introduced genetic constructs reach the target cells and, getting into them, are expressed there in the corresponding protein products.

In contrast, in ex vivo gene therapy, the necessary cells are first " withdrawn "from the patient, and the genetic material is injected into them in vitro (that is, in the laboratory), after which such cells are" multiplied " in a Petri dish to a sufficient amount and injected back to the patient. It is obvious that ex vivo gene therapy is also a cell therapy, since it uses the transplantation of genetically modified cells into the human body.

Carrier vectors for gene delivery

In most cases, viruses are used as carriers for gene delivery, whose natural ability to introduce their genetic material into the host cells can be not only harmful, but also useful. But everything is not as scary as it seems: such viruses are first "dissected" by genetic engineering methods, removing most of the genes responsible for virulence, which does not allow the virus to divide uncontrollably and frees up space for inserting the target gene that needs to be delivered to the cell. These carrier viruses do everything the same as before, but only for the benefit of the patient's health: they protect the therapeutic gene from cleavage by blood enzymes, force target cells to capture the virus, separate nucleic acid from the viral particle and transport it to its destination (usually to the cell nucleus). A cell that has "caught" such a virus turns out to be infected ― but not with a dangerous infection, but with a gene that treats the disease ― and therefore begins to synthesize a new protein that guides the cell along the path of healing.

Gene therapy today

Today, we are closer than ever to entering a new era of gene therapy, because many drugs of this class for use for various indications are already at different stages of clinical trials (of which more than two thousand have been registered). Nevertheless, since gene therapy initially encountered serious obstacles and failures on the way to introduction into the clinic, as well as due to the complexity of development, very few such drugs have been approved for the actual treatment of patients so far.

A look into the future

Gene therapy using viral vectors will certainly continue to improve, and we will see new drugs based on this technology in the clinic. However, there are solutions that theoretically can enhance the potential of gene therapy, which, perhaps, in the future will make it not only much safer and more effective, but also applicable to more common diseases (however, while such achievements are far away, we will not get too far ahead).

We are talking about point editing of the genome, which received a second life in 2012 with the development of the CRISPR/Cas9 tool — a technology originating from the natural system of protecting bacteria from viruses (bacteriophages), but adapted by researchers to their needs, and now a popular tool for genetic manipulation. This method is relatively easy to use, has a fairly high accuracy, and therefore has managed to find application in a variety of fundamental research, including experiments on cell lines, laboratory animals, plants, and now in clinical trials of gene therapy based on it.

Limitations of gene therapy

Gene therapy technologies are at the very beginning of the path, so, naturally, they have a lot of" childhood diseases " and a huge scope for improvement. The main tasks that need to be solved are listed below:

  1. complexity, labor intensity, high cost and, as a result, poor scalability of the technology, which is why gene drugs are still incredibly far from mass production (and it's not a fact that they will approach it soon);
  2. the exorbitant cost of such treatment resulting from the previous paragraph, which is why it is available only to a few;
  3. often serious adverse events of a new type, sometimes even leading to irreversible consequences (up to a fatal outcome). However, as they gain experience, doctors are already learning to cope with them;
  4. insufficient observation period for the use of gene therapy, hence there is uncertainty about the long-term effect of its effect, as well as concerns about the possible long-term consequences of the use of such drugs;
  5. Imperfection of the target gene delivery technology: the viral vectors that are most often used are far from ideal. In addition to the mentioned problems with non-targeted integration into the genome (characteristic of lentiviral and gamma-retroviral vectors), there is also a danger of activation of the immune system (for AAV vectors), which reduces the efficiency of delivery of target genes. At the same time, the repeated introduction of the vector is not always possible.

However, these are not only problems: these are also potential "growth points" for a new technology, where new ideas get a chance to be realized in the form of a tangible advantage.

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