AUGMENTATION GENE THERAPY

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AUGMENTATION GENE THERAPY

In this type of somatic cell gene therapy, the functional gene is introduced in addition to the defective gene endogenous to cell(s) i.e., the modified cells contain both defective as well as normal copies of the gene. There are 2 general approaches to augmentation therapy.

The first approach was used in the first 2 patients on whom gene therapy was attempted to correct the genetic disorder SCID produced by adenosine deaminase deficiency.

Normal ADA gene copies were produced by by cloning & then
packed into retrovirus; most of the viral genes were replaced by the ADA genes.
Lymphocytes were isolated from the patients, &
the recombinant retroviruses were used to infect the lymphocytes.
Finally the infected cells expressing the ADA gene were injected back into the patients.

The normal ADA gene was expressed in the patients, & ADA deficiency was partially corrected; this resulted in an improvement of inherited blood disorders like Hemophilia, Thalassemia, etc.

A variety of viral factors have been used to deliver genes target stem cells, e.g., lymphocytes, bone marrow cells, cultured in vitro.

The main problems approach are as follows:

Low frequency of transfection of stem cells,
Stability of the integrated gene,
duration of the gene expression,
Lack of proper gene expression, etc.

The second approach is the direct injection of DNA into the tissues either as protein complexes or even as naked DNA into the muscle or skin. Interestingly these cells take up the DNA 7 express the gene product. Exciting results have been obtained with experimental hypercholesterolemia, where LDL receptor levels have been augmented by injection of the gene as sialoglycoprotein complex . This approach has the considerable promise to treat lung disorders like cystic Fibrosis.

However the problem with this approach as well relate to frequency of cells taking up & expressing the gene & more particularly, the duration of expression, which is at best only a few weeks.