Applications of Gene Therapy

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Chapter: Essential pharmacology : Immunosuppressant Drugs, Gene Therapy

Diverse applications of gene therapy are being pursued— mostly in experimental animals, but some have been tried clinically. Inherited single gene disorders appear simpler to correct or cure. In addition, several innovative strategies against cancer, viral diseases, acquired lifestyle diseases, etc. are being applied.


APPLICATIONS OF GENE THERAPY

 

Diverse applications of gene therapy are being pursued— mostly in experimental animals, but some have been tried clinically. Inherited single gene disorders appear simpler to correct or cure. In addition, several innovative strategies against cancer, viral diseases, acquired lifestyle diseases, etc. are being applied. The prominent ones are:

 

·    Cystic fibrosis: by insertion of cystic fibrosis transport regulator (CFTR) gene into respiratory epithelial cells. This gene regulates expression of an apical chloride channel which is dysfunctional in cystic fibrosis. The limitation is that airway epithelial cells are rapidly shed off.

 

·  Severe combined immunodeficiency disease (SCID): by introducing gene for adenosine deaminase which is deficient.

 

·       Growth hormone deficiency: by implanting cultured myoblasts transfected with GH gene.


·  Familial hypercholesterolemia: by introducing LDL receptor gene into hepatocytes.


· Lesch-Nyhan syndrome: by introducing hypoxanthine phosphoribosyl transferase gene to correct deficiency of this enzyme in the CNS which causes severe neuropsychiatric disorder.

 

·   Parkinsonism: by introducing the gene for tyrosine hydroxylase to augment dopamine production in basal ganglia.

 

·     Alzheimer’s disease, Huntington’s chorea, familial amyotrophic lateral sclerosis, Gaucher’s disease: by supplementing the defective genes.

 

·  Stroke, head injury, multiple sclerosis: by delivering nerve growth factor gene.


· Duchenne muscular dystrophy: by administering muscle dystropin gene.


·      Cancer:

 

a.        By genetic introduction of an enzyme (viral thymidine kinase) into tumour cells followed by a prodrug that is converted to the toxic metabolite— tumour cells are selectively killed.

 

b.       By inserting TNFα, IL2 and other cytokine genes into tumour cells to increase their immune recognition and destruction by tumour infiltrating lymphocytes.

 

c.        By introducing promoter ‘antisense’ gene or ‘suppressor’ gene which negatively regulate tumour growth.

 

d.    By introducing multi-drug resistance MDR1 gene into bone marrow cells and render them less susceptible to destruction by myelo-suppressant drugs. Thus, a limiting toxicity of many anticancer drugs can be overcome.

 

·  Prevention of restenosis of grafted coronary vessels: by introducing genes which inhibit growth of intimal cells.


·  Anaemia: by myoblast mediated introduction of human erythropoietin gene.


·  Sickle cell anaemia: by introducing beta/delta sickle cell inhibitor hybrid gene.


·       Haemophilia: by introducing factor VIII gene.

 

·   Insulin dependent diabetes mellitus: by introducing insulin1 gene into liver to act as an ectopic site for insulin production.

 

·     HIV infection: by injecting fibroblasts expressing HIV envelope glycoprotein gene to augment immunity against HIV.

 

However, as yet gene therapy is only a research modality and in clinical trial stage. A number of technological, toxicological and ethical problems have to be solved before it could be available for mass application.

 

Another promising approach is to block expression of particular defective gene by antisense oligonucleotides, which are 15–25 base pair single strand nucleotides that interact with certain segments of specific genes and prevent their translation. Fomivirsen is an antisense oligonucleotide which has been approved for use in CMV retinitis.


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