F4 Gene therapy | 52 | v4 | BIOS Instant Notes in Genetics

ABSTRACT

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Overview

It is now possible to treat genetic disorders by the addition of functional copies of the gene responsible for the disorder. This is, at present, limited to treating somatic cells. Germ cell gene therapy is considered unethical. The major problem in developing gene therapies is finding the optimal vector to transfer the therapeutic gene into the recipient's cells. Gene therapy can be carried out on the whole patient (in vivo therapy) or on cells which have been removed from the patient and which are then returned after the gene has been added (ex vivo therapy). In some disorders the therapeutic gene will have to be targeted to a particular cell type, while for other syndromes several tissues may make suitable targets. In the last decade gene therapy methods have begun to yield clinical successes.

Vectors

Viruses offer the best potential as vectors in gene therapy. The bulk of viral genes are removed to prevent virus replication in the patient. Retroviruses infect most cell types, but only if the cells are dividing. This limits their use to ex vivo application. Lentiviruses may prove a more useful alternative. Adenoviruses can also be used but their DNA does not integrate into the target cell's chromosomes and their effect is transient. They also may induce immune response in the patient. An alternative to the use of viral vectors involves encapsulating DNA in liposomes. This causes no side effects, but is much less effi cient in transferring DNA to target cells.

Severe combined immunodeficiency syndrome

The genes for adenine deaminase or IL2RG can be introduces into homopoietic stem cells removed from patients with this disease using a retrovirus vector. When the stem cells are reintroduced into patients most show enhanced levels levels of immune response and this level is stable for several years. A small number of patients have developed leukemia after treatment.

Hemophilia

Hemophilia is a good candidate for gene therapy because the clotting factors simply need to circulate in blood, it doesn't matter which cells make them. Experiments with Factor IX have worked in animal models but only inadequately in human trials.

Cystic fibrosis

Gene therapy for this disease has to be carried out in vivo because the major target tissue is the lining of the lungs. Adenovirus vectors have been used. These cause side effects and may be of limited use. An alternative approach is to use liposomes.

Cancer

This is currently the major area of medicine in which gene therapy is being used. There are a number of different approaches. These include introducing genes to kill tumor cells, or to stimulate the response of the host. One potentially useful method involves the use of the herpes simplex thymidine kinase gene to sensitize the tumor cells to drug treatment. Genetically modified T lymphocytes have been used to successfully treat some leukemias.

Vision defects

Gene therapy is currently being used to treat patients with Leber's congenital amaurosis. Some increase in sight has been reported.