19.2.3 Gene Therapy

• Gene therapy involves using various mechanisms to alter a person's genetic material to treat, or cure, diseases
• As scientists gain a better understanding of the human genome and therefore the location of genes that cause genetic disorders, the possibilities of gene therapy being able to replace a faulty gene, inactivate a faulty gene or insert a new gene are growing
• Experimental techniques are being used to treat and research treatments for genetic diseases such as severe combined immunodeficiency (SCID), Leber congenital amaurosis – a rare form of blindness, β-thalassaemia and haemophilia B
• Most gene therapies are still in the clinical trial stage because scientists are having difficulty finding delivery systems that can transfer normal alleles into a person’s cells and how to ensure the gene is correctly expressed once there
• Finding an appropriate delivery system has been one of the problems. Vectors are currently used as the delivery system, with viruses being the most commonly used, but non-viral vectors are also being researched (eg. liposomes and ‘naked’ DNA)
• Viruses (eg. retroviruses and lentiviruses) are the most commonly used vectors as they have the mechanisms needed to recognise cells, and deliver the genetic material into them

• Changes in genetic material are targeted to specific cells and so will not be inherited by future generations (as somatic gene therapy does not target the gametes)
• Often the effects of changing the somatic cells are short-lived
• There are two types of somatic gene therapy:
  • Ex vivo – the new gene is inserted via a virus vector into the cell outside the body. Blood or bone marrow cells are extracted and exposed to the virus which inserts the gene into these cells. These cells are then grown in the laboratory and returned to the person by an injection into a vein
  • In vivo – the new gene is inserted via a vector into cells inside the body

• There is the potential for new genetic material to be inserted into germ cells (cells involved in sexual reproduction eg. gametes or an early embryo)
• However, this is illegal in humans as any changes made to the genetic material of these cells is potentially permanent and could therefore be inherited by future generations

The two types of somatic gene therapy - ex vivo and in vivo. Two of the methods scientists are using to alter a patient’s genetic material to treat or cure diseases

Severe combined immunodeficiency (SCID)

• Severe combined immunodeficiency (SCID) is caused by the body's inability to produce adenosine deaminase (ADA), an enzyme that is key to the functioning of the immune system. Without this enzyme children can die from common infections and therefore need to be keep isolated often inside plastic ‘bubbles’
• To treat SCID scientists have used ex vivo somatic gene therapy. During this therapy, a virus transfers a normal allele for ADA into T-lymphocytes removed from the patient and the cells are then returned via an injection
• This is not a permanent cure as the T-lymphocytes are replaced by the body over time and therefore the patient requires regular transfusions every three to five months to keep their immune systems functioning
• Originally retroviruses were used as the vectors, however these viruses insert their genes randomly into a host’s genome which means they could insert the gene into another gene or into a regulatory sequence of a gene (which could result in cancer)
• Initial treatments did cause cases of leukaemia in children, so researchers switched to using lentiviruses or adeno-associated viruses as vectors. Lentiviruses also randomly insert their genes into the host genome however they can be modified to not replicate, whereas adeno-associated viruses do not insert their genes into the host genome and therefore the genes are not passed onto the daughter cells when a cell divides. This is an issue with short-lived cells like lymphocytes but has not been a problem when used with longer living cells such as liver cells

Inherited eye diseases

• An example of a group of inherited eye diseases that causes blindness due to damage to the light receptors in the retina are Leber Congenital Amaurosis. It begins to affect children from birth and by their 20s or 30s the person is totally blind. There is no cure for these diseases
• Using in vivo somatic gene therapy, doctors injected into the retina adeno-associated viruses that contained the normal alleles of one of the genes that caused damage to the photoreceptors (there are at least 18 known mutated genes causing this group of diseases). All patients that have had the injections have shown improvement in their eyesight