Gene Therapy

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Chapter: Essential pharmacology : Immunosuppressant Drugs, Gene Therapy

Gene therapy refers to the introduction of functional genetic material into target cells to replace or supplement defective genes, or to modify target cells so as to achieve therapeutic goals.



Gene therapy refers to the introduction of functional genetic material into target cells to replace or supplement defective genes, or to modify target cells so as to achieve therapeutic goals. In contrast to all other drugs, this kind of therapy can impart new functions to a cell. Conceived in the 1960s and started in the 1980s gene therapy is still experimental, but holds great promise for curing a number of diseases which at present can, at best, be only palliated or controlled. Gene defects result in failure to synthesize a functional protein or in the synthesis of a dysfunctional protein. Equipping the cell (especially the one which physiologically expresses it) with a normal copy of the defective gene would overcome the deficiency at the site where it is needed on a long-term (may be permanent) basis. Apart from inherited genetic disorders with single nucleotide polymorphism (SNP), the major thrust area of gene therapy are a number of acquired diseases such as malignancies, immunological disorders, including AIDS, cardiovascular, neurological and infective diseases, in many of which even shortterm expression of the introduced gene could be therapeutic.





Gene therapy endeavours to either modify or transfer genes.


1. Gene Modification


This involves correction of the defective portion of a genomic sequence or removal of the whole defective gene and its replacement by the normal copy, or alteration of the sequences controlling its expression. These are technically quite difficult in the in vivo setting.


2. Gene Transfer


This involves introduction of one or more genomic expression cassettes without removing or altering the existing ones. Significant progress has been made in this approach. Gene transfer is carried out by using various physical, chemical or biological delivery methods (vectors).


Physical Methods: are microinjection in a single cell, introduction of DNA complexed with gold pCh. No.s/ dextran/lipids, use of microprojectiles or direct parenteral injection of uncomplexed DNA. However, efficiency of gene transfer is low and duration of expression is short.


Chemical Methods use liposomes or other specific cellular ligands. The liposomes can carry genes to the intracellular location in large amounts, are nonimmunogenic and technically simpler, but the level of gene transfer achieved is lower than by use of viral vectors. Liposomal delivery has been used in certain human gene therapy trials.


Biological Methods involve fusion of recipient cell with bacterial spheroplasts, erythrocyte membrane vesicles, whole cell fusion, etc, but the most efficient and widely used are the viral vectors. Adenoviruses, Lenti virus, Herpes simplex virus have been utilized, but retroviruses are the most popular vectors. For using viral vector, its ‘gag’, ‘pol’, and ‘env’ genes which carry out viral replication are removed and replaced by the genes to be transferred using recombinant DNA technology. These viral pCh. No.s are then introduced into a packaging cell line previously equipped with the ‘gag’, ‘pol’, and ‘env’ genes which then produce multiple viral pCh. No.s carrying the desired gene. The retroviral vector is then allowed to infect host cells so that the desired DNA is inserted into a random site in the host genome which subsequently expresses the transferred gene. However, the duration of expression of the transferred gene is variable.


Gene transfer could be carried out into:


·       Germline cells The new gene is introduced into embryonal cells so that it passes into the next generation. This is ethically not applicable to humans at present.


·            Somatic cells Certain somatic cells like the bone marrow stem cells, fibroblasts, hepatocytes or myocytes of the recipient receive the new gene. This is being extensively pursued.


·       Specific organ directed delivery of genes to the tissues that actually require it is being tried. Success has been achieved in transferring genes into liver cells, vascular smooth muscle and endothelial cells, pulmonary cells, etc.


The techniques of gene therapy may utilize either ex vivo or in vivo gene transfer.


Ex vivo gene transfer: The patient’s tissue cells are isolated and maintained in tissue culture. These are then transfected with the vector carrying the relevant gene and injected back into the patient. This method has been widely utilized in the treatment of single gene defects, metabolic, haematological and immune disorders.


In vivo gene transfer: The vector, usually a retrovirus carrying the gene is injected systemically or directly into the concerned organ. The property of retrovirus to transduce only dividing cells, such as tumor cells, is utilized for selective delivery of the gene leaving nondividing cells unaffected. However, this is a relatively inefficient method of gene therapy.


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