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In this article, we will discuss how genetic diseases can be treated with gene therapy. To do so, we will use examples of severe combined immunodeficiency (SCID) and inherited eye diseases.
Gene Therapy
What is Gene Therapy?
Gene therapy refers to the repair or replacement of faulty genes with healthy versions. It is done by introducing DNA containing functional genes into a patient which rectifies the disease-causing mutation.
Different mechanisms are included in gene therapy to modify the genetic material of the person. The purpose of gene therapy is to treat or cure diseases. Because scientists are understanding the human genome better than ever, hence the location of the genes that cause genetic diseases, the possibility of replacing the faulty gene through gene therapy, inactivating the faulty gene, or inserting a new gene is increasing.
Which techniques are used by the scientists?
To treat and discover treatments for genetic diseases like severe combined immunodeficiency (SCID), Leber congenital amaurosis which is a rare kind of blindness, β-thalassemia, and haemophilia B, scientists are using experimental techniques.
What problems do scientists face?
Since scientists are facing difficulty in finding delivery systems that can transport normal alleles into a person’s cells and ensure the correct expression of the gene over there, hence the majority of the gene therapies are still in the clinical trial stage. Another problem faced by scientists is finding a suitable delivery system. Although vectors are used as a delivery system, among which viruses are most common, however, research is also conducted on using non-viral vectors like liposomes and naked DNA. Since viruses possess the mechanisms that are required to identify cells and deliver the genetic material to them, hence they are most commonly used today.
What is somatic gene therapy?
Modifications in genetic material are targeted to the specific cells, hence they cannot be inherited by future generations. This is because gene therapy does not target gametes. Most of the time, the effects of changing the somatic cells are short-lived. Somatic gene therapy is of two types:
- Ex vivo: It involves the insertion of the new gene through a virus vector into the cell outside the body. It includes the extraction and exposure of blood or bone marrow cells to the virus which inserts the gene into these cells. After that, these cells are grown in the laboratory and returned to a person through an injection into a vein.
- In vivo: It involves the insertion of the new gene through a vector into the cells inside the body.
There is a possibility of inserting the new genetic material into the germ cells (These cells are involved in sexual reproduction, for instance, gametes or an early embryo). However, in humans, it is illegal because any modifications in the genetic material of these cells can be permanent and hence transferred to future generations.
Severe combined immunodeficiency (SCID)
What is SCID?
When the body cannot produce adenosine deaminase (ADA) enzyme, then an individual gets a disease known as severe combined immunodeficiency (SCID). ADA enzyme is critical for the functioning of the immune system. The absence of this enzyme can prove fatal for children as they are more likely to get common infections. Hence, such children are often kept isolated inside plastic bubbles.
How is SCID treated?
Scientists employ ex vivo somatic gene therapy to treat SCID. During this therapy, a virus is used as a vector to transfer a normal allele for ADA into T-lymphocytes removed from the patient and the cells are then returned through an injection.
Does this therapy treat this disease permanently?
No, this is not a permanent cure because the T-lymphocytes get replaced by the body gradually and hence the patient needs regular transfusions every three to five months for the proper functioning of the immune system.
Issues with retroviruses as vectors
Traditionally, retroviruses were employed as vectors, however, these viruses used to insert their genes randomly into the host’s genome. It implies that they could insert the gene into another gene or into a regulatory sequence of a gene that can cause cancer.
In the beginning, the treatments caused cases of leukaemia in children. Hence the researchers switched to using lentiviruses or adeno-associated viruses as vectors. Although lentiviruses also insert their gene randomly into the host genome, however, they can be altered to prevent replication. On the other hand, adeno-associated viruses do not insert their genes into the host genome and hence the genes are not transferred to the daughter cells when a cell divides. This issue arises when short-lived cells such as lymphocytes are used. On the other hand, the issue is not faced when longer living cells such as liver cells are used.
Inherited Eye Diseases
Leber Congenital Amaurosis is an example of a group of inherited eye diseases that result in blindness because of the damage occurred to the light receptors in the retina. It starts to affect the children from their birth and when they reach their 20s or 30s, they get blind completely. Unfortunately, there is no cure for these diseases.
How in-vivo somatic gene therapy is used to treat this group of diseases?
By employing in-vivo somatic gene therapy, doctors injected adeno-associated viruses into the retina that carried the normal alleles of one of the genes that caused damage to the photoreceptors. A minimum of 18 known mutated genes are known to cause this group of diseases. It was observed that the eyesight of all the patients who got these injections improved.
Challenges of Gene Therapy
Although fundamental gene therapy is quite straightforward, however, many technical, ethical, and biological challenges are associated with it. For gene therapy to be successful and to prevent its negative consequences, the gene must be delivered to the right place and the cells should use it appropriately. Similarly, it is vital to take care that the gene is not inserted into a place where it can disturb the function of other genes.
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