Gene Therapy

Every cell in our body contains chromosomes, each of which holds DNA containing genetic information in the form of genes. Genes play a crucial role in coding for proteins that serve various functions, including instructing the body to perform specific actions such as muscle growth and determining our physical characteristics. Genes exert control over many aspects of our body, but when they contain errors or mutations, they can lead to diseases and bodily harm. This is how conditions like cancer, Alzheimer's disease, and Down syndrome can develop.

Gene therapy is a current approach used to address these issues. It involves inserting DNA into a cell to either reduce the production of disease-causing proteins or increase the production of disease-fighting proteins. The desired DNA is delivered into the cell's nucleus through two distinct methods: in vivo and ex vivo. In vivo entails directly introducing the desired gene into the body through an injection, while ex vivo involves extracting a cell from the body, modifying its genetic material, and then reintroducing it into the body. This gene is transported into the nucleus with the assistance of specific viruses known as viral vectors. These viruses are adept at penetrating the nucleus and infecting the cell, although they do not harm the body. As a result, the DNA successfully integrates into the nucleus, where it becomes active and begins producing the desired protein.

Example of in exon gene therapy (Source)

Stem cells found in our bone marrow play a significant role in gene therapy as they possess the remarkable ability to differentiate into any cell type in our body. Gene therapy capitalizes on this capability by introducing DNA into stem cells and guiding their transformation into the specific missing cell type required to produce necessary proteins.

Gene therapy has the potential to address conditions like achromatopsia, an inherited retinal eye disease characterized by extreme light sensitivity and color loss. Individuals with achromatopsia lack cone photoreceptor cells within the retina responsible for converting light into electrical signals transmitted to the brain. This condition arises due to mutations in the CNGB3 and CNGA3 genes. Gene therapy offers a solution by introducing functional CNGB3 and CNGA3 genes to replace the nonfunctional ones, enabling patients to regain their vision.

A recent FDA-approved gene therapy medication called Vyjuvek utilizes vector-based gene therapy to treat dystrophic epidermolysis bullosa (DEB), a rare and severe genetic skin disorder caused by mutations in the COL7A1 gene. Vyjuvek gel is injected into the wound site, promoting the binding of COL7 molecules to facilitate blister closure, addressing what the body's original COL7A1 gene couldn't achieve. It is worth noting that this form of gene therapy substitutes the faulty mutated gene with a newly created one, rather than addressing the root cause of the genetic issue.

A visual of the effects of DEB (Source)

While gene therapy holds the potential to address numerous genetic diseases and malfunctioning genes, it remains largely inaccessible to the general public due to several significant implications. The primary concern is the exorbitant cost associated with gene therapy, with the average dose ranging from 1 to 2 million dollars. Such an unaffordable price tag poses a significant barrier to the advancement of gene therapy, as it hampers widespread interest and accessibility. However, cost is not the sole issue. Gene therapy may sometimes lead to unintended complications, including incorrect cell targeting, viral infections, unwanted immune responses, and various other potential side effects.

But what limits gene therapy from realizing its full potential? To date, scientists have primarily employed gene therapy by introducing DNA information to compel the body to perform functions that mutated cells cannot. Gene editing, a distinct form of gene therapy, offers a more promising solution. Gene editing aims to rectify the root cause of genetic diseases by replacing erroneous DNA sequences with the correct form or entirely deactivating problematic DNA sequences through multiple methods, thereby preventing mutations from occurring in the first place. Gene editing is a more precise approach, though it is still in the early stages of research and has not been as widely utilized as it should be.

A diagram describing the process of the Csa9 enzyme (Source)

Gene editing via the CRISPR-Cas9 system occurs with two parts: the CRISPR-Cas9 enzyme and a guide RNA. The CRISPR-Cas9 enzyme along with the guide RNA is able to cut specific cuts in the DNA, leading to either deletion or complete shutdown of the targeted gene. Corrections of the DNA can also be performed when a correct gene is injected after the Cas9 enzyme deletes the replaceable mutated part of the gene. There are two different forms of gene editing: somatic gene editing and germline gene editing which are processes where DNA is altered within blood cells and reproductive cells respectively.

Table explaining the major and notable differences between somatic and germline editing (Source)

Gene editing also has downsides such as being able to cause more mutations within the patient if the CRISPR-Cas9 performs its cuts and replacements in the wrong section of a gene. Not only will the original mutation not be cured, more mutations will occur within the patient's body which will most likely be inheritable, especially if the CRISPR-Cas9 performs on sperm or egg cells. This brings up ethical issues as attempting to free yourself from a mutation (that is caused by a gene present within the germline) with disregard to your descendants has the possibility of creating a worse life for the patient's children. This caused congress and many other countries to take action and ban germline gene editing, which is the act of making genetic modifications to gamete precursor cells, eggs, sperm, or early-stage embryos.

Detailed image displaying the function and layout of a CRISPR-Cas9 enzyme (Source)

Gene editing certainly has much to be learned about and has potential applied into our lives. In the future where we are able to control the CRISPR-Cas9 enzyme, much more possibilities of gene editing would open up as scientists would be able to solve more genetic mutations and create the process more accessible to the public.

Resources

1. Gene editing

2. How CRISPR Is Changing Cancer Research and Treatment - NCI

3. Harvard researchers share views on future, ethics of gene editing

4. The Potential Revolution of Cancer Treatment with CRISPR Technology - PMC.

5. FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa.

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Impact Statement

Cancer is fundamentally a disease of gene expression and regulation. Research has focused on the pathways around promoting cell division (e.g. Ras and the promotion of excessive cell division) or the pathways around inhibiting cell growth. Multiple gene mutations are typically required before the development of cancer.

_By: Ryan Yun_

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.