Genes, which are carried on chromosomes, are the basic

physical and functional units of heredity. Genes are specific

sequences of bases that encode instructions on how to make

proteins. Although genes get a lot of attention, it’s the proteins

that perform most life functions and even make up the majority of

cellular structures. When genes are altered so that the encoded

proteins are unable to carry out their normal functions, genetic

disorders can result. Gene therapy is a technique for correcting defective genes

responsible for disease development. There are several

approaches for correcting the faulty genes.

Gene Therapy

Defective Gene – Genetic Disorder

Gene is said to be defective if there is change in the inherited

gene. It is clear that any heritable change in a gene is brought

about by mutation. Mutation can be defined as any change in the

base sequence of the DNA. The consequences of mutation is-

# premature termination in the growth of the peptide chain,

# synthesis of non-functional protein. In either events, the absence of the normal protein can lead to a

variety of clinical manifestations depending on the structural or

enzymatic role that normally plays in the cell. Such conditions

range from mild disorders that require no treatment (e.g., color

blindness) to life threatening disease (e.g., hemophilia, cystic

fibrosis).

Over 45,000 human diseases have been identified related

directly to the genetic disorders.

Defective Gene – Genetic Disorder

Treatment of Genetic Disorders-Gene therapy versus conventional therapy

Limitations of the conventional therapy

Therapy based on the replacement of the missing or defective

protein is available for only a few of these disorders. Example:

Factor VIII for hemophilia, adenosine deaminase for SCIS,

transfusion for sickle cell disease.

Limitations of the conventional therapy

Conventional therapies are only partially effective in ameliorating the manifestations of the disease and are accompanied by significant complications.

For most genetic disease, providing the missing protein in a therapeutic fashion is not feasible due to the complex and fragile nature of the protein and the need to deliver the protein to a specific subcellular localization (i.e., cell surface expression, lysosomal localization, etc.).

Transplantation of the major affected organ has been done in some instances (e.g., bone marrow transplantation for sickle cell disease, liver transplantation for hyperlipidemia), but this has also severe limitations of organ availability and adverse consequences arising from the immune suppression required to prevent rejection of an allogenetic tissue.

Providing a normal copy of the defective gene to the affected tissues

would circumvent the problem of delivering complex proteins, as the

protein could be synthesized within the cells using the normal cellular

pathways.

The limited number of tissues are affected by most inherited disorders,

this greatly simplifies the requirements for effective gene therapy,

since a functional copy of the gene need to be provided only to those

tissues that actually require it. So gene therapy is generally applied to

correct defect in only part of the body and thus targeting of the

therapeutic gene to a specialized area is important in gene therapy.

If the gene transfer can be targeted to the major affected organs, thus

side effects arising from ectopic gene expression in nontargeted cells

might be avoided.

Problems overcome by gene therapy

As with other pharmaceutical agents, cell-specific targeting has the

advantage of decreasing the effective volume of distribution and

the amount of gene transfer agent needed.

The majority of gene therapy trials underway are for the treatment of

acquired disorders such as AIDS, cancer, CVS and inherited disorder

arising from single gene defects, such as AD, LSD, etc.

In case of inherited disorder, the defective gene that cause the

disorder is the subject of intervention, and-

In the case of acquired diseases, either a defective gene that

contributes to the disorder or a gene that mediates an unrelated

biochemical process may be the basis for intervention. Example:

Treatment of HIV infection potentially could rely on the interruption of

viral processes that contribute to the pathogenesis of AIDS, antisense

mRNA, a dominant negtaive mutant protein.

Where is gene therapy applied?Where is gene therapy applied?