Gene TherapyGene Therapy

Tapeshwar Yadav(Lecturer)BMLT, DNHE,

M.Sc. Medical Biochemistry

A Brief History of Gene Therapy

Advances in biochemistry and molecular biology have helped to understand the genetic basis of inherited diseases.

Gene therapy was once considered a fantasy (imaginary).

It was a dream of the researchers to replace the defective genes with good ones and cure the genetic disorders.

Contd…

However, thousands of individuals have already undergone human clinical trials.

A great leap in medical science has taken place on the 14th September 1990, when a girl suffering from Adenosine deaminase deficiency (Severe immunodeficiency) was treated by transferring the normal gene for adenosine deaminase.

What is Gene Therapy?It is intracellular delivery of genes to generate

a therapeutic effect by correcting an existing abnormality.

Only somatic gene therapy, by inserting the new gene into somatic cell of the patient is under trail.

Germ cell gene therapy is considered as unethical.

NOTE:- Gene therapy is the process of inserting normal genes into cells to treat diseases.

Gene therapy strategies

1. Gene augmentation therapy:- A DNA is inserted into the genome to replace

the missing gene product.2. Gene inhibition therapy:- The antisense gene inhibits the expression of

the dominant gene.

Approaches for Gene Therapy

Two approaches to achieve gene therapy:-1.Somatic cell gene therapy2.Germ cell gene therapy

1.Somatic cell gene therapy: The non-reproductive (non-sex) cells of an organism

are referred to as somatic cells. These are the cells of an organism other than sperm

or egg cells, e.g.- bone marrow cells, blood cells, skin cells, intestinal cells.

At present, all the research on gene therapy is directed to correct the genetic defects in somatic cells.

It involves the insertion of a fully functional and expressible gene into a target somatic cell to correct a genetic disease permanently.

2.Germ cell gene therapy:

The reproductive (sex) cells of an organism constitute germ cell line.

Gene therapy involving the introduction of DNA into germ cell is passed on to the successive generations

Ethical and technical reasons, germ cell gene therapy is not being attempted at present.

Types of gene therapy

Ex vivo gene therapy involves the transfer of genes in cultured

cells (e.g., bone marrow cells) which are then reintroduced into the patient.

In vivo gene therapy the direct delivery of genes into the cells

of a particular tissue is referred to as in vivo gene therapy

Technique of ex vivo gene therapy

Isolate cells with genetic defect from the patient.

Grow the cells in nature.Introduce the therapeutic gene to correct

gene defectSelect the genetically corrected cells and growTransplant the modified cells to the patient.

Vectors in Gene Therapy

Viruses i.e. retroviruses

Human artificial Chromosomes

Bone marrow cells i.e. totipotent embryonic stem cells

IN VIVO GENE THERAPY Direct delivery of the therapeutic gene (DNA) into

the target cells of a particular tissue of a patient constitutes in vivo gene therapy.

Gene delivery can be carried out by viral or non-viral vector systems.

Success of in vivo gene therapy mostly depends on-o Efficiency of the uptake of the remedial (therapeutic)

gene by the target cells.o Intracellular degradation of the gene and its uptake by

nucleus.o Expression capability of the gene.

Human Gene Therapy TrialsDisease Gene therapy

Severe combined immunodeficiency (SCID)

Adenosine deaminase (ADA)

Cystic fibrosis Cystic fibrosis transmembrane regulator (CFTR)

Familial hypercholesterolemia LDL receptor

Thalassemia α- or β-globin

Sickle cell anaemia β-globin

Lech-Nyhan syndrome HGPRT

Breast cancer Multi drug resistance I

Short stature Growth hormone

Diabetes GLUT-2, glucokinase

Phenylketonuria Phenylalanine hydroxylase

Citrullinemia Arginosuccinate synthetase

FUTURE OF GENE THERAPY

Theoretically, gene therapy is the permanent solution for genetic diseases.

But it is not as simple as it appears since gene therapy has several inbuilt complexicities.

Gene therapy broadly involves isolation of a specific gene, making it’s copies, inserting them into target tissue cells to make the desired protein.

The story does not end here.

Contd…

It is absolutely essential to ensure that the gene is harmless to the patient and it is appropriately expressed (too much or too little will be no good).

Another concern in gene therapy is the body’s immune system which reacts to the foreign proteins produced by the new genes.

Contd…The public, in general, have exaggerated

expectations on gene therapy. The researchers, at least for the present, are unable

to satisfy them. As per the record, by 1999 about 1000 Americans

had undergone clinical trails involving various gene therapies.

Unfortunately, the gene therapist are unable to categorically claim that gene therapy has permanently cured any one of these patients!

Some people in the media have openly questioned whether it is worth to continue research on gene therapy!!

Contd…It may be true that as of now, gene therapy due

to several limitations, has not progressed the way it should, despite intensive research.

but a breakthrough may come anytime, and of course, this is only possible with persistent research.

And a day may come (it might take some years) when almost every disease will have a gene therapy, as one of the treatment modalities.

And gene therapy will revolutionize the practice of medicine!