Human gene
therapy can be defined as the transfer of exogenous genes or nucleotide
sequences into somatic cells for the purpose of preventing, correcting or
healing various diseases.
Somatic gene
therapy is a new type of weapon in the fight against acquired diseases.DNA is
considered as a drug providing a framework for curing thousands of genetic
diseases. It also satisfies one of the greatest dreams of clinical medicine: ‘molecular surgery’ at the root of the
disease.
Cystic fibrosis (CF)
People
suffering from cystic fibrosis lack CF gene needed to produce a salt-regulating
channel protein, cystic fibrosis
transmembrane conductance regulator (CFTR). This protein regulates the flow
of chloride in to epithelial cells that cover the air passages of the nose and
lungs. Without this regulation, patients with CF disease build up thick mucus
that makes them prone to chronic lung disease. The gene
therapy technique to correct this abnormality might employ an adenovirus to transfer
a normal copy of the CFTR gene. The gene is introduced into the patient by
spraying into the nose.
Familial hypercholesterolemia (FH)
The patients
with genetic disorder unable to process cholesterol properly by a low density lipoprotein receptor(LDLR),
which leads to high levels of fat in the blood stream. Patients with FH disease suffer from heart
attacks and strokes because of blocked arteries. A gene
therapy approach is developed with partial removal of patient’s liver. Corrected
copy of a gene is inserted into liver sections, which are transplanted back
into patients. The healthy gene may reduce the cholesterol build-up in the
blood of the patient.
Duchene muscular dystrophy (DMD)
DMD is the
most common childhood form of muscular dystrophy because of the failure to
express dystrophin in the muscle fibres. It is a lethal, recessive X-linked
disorder, more frequent in males. Muscular dystrophy is characterized by
progressive muscle weakness, defects in muscle proteins and death of muscle
cells and tissue. Viral mediated in vivo
gene transfer method was developed to deliver dystrophin gene to patient’s
muscle. Simple non-viral gene transfer in
vivo was also developed using naked plasmid DNA.
Cancer therapy
In general,
cancers have at least one mutation to a proto-oncogene (yielding) an oncogene)
and at least one to a tumour suppressor gene allowing the cancer to proliferate.
Oncogene inactivation may be targeted at the level of DNA, RNA transcription or
protein product. Oligonucleotides are designed in sequence specific manner to
target the promoter regions of oncogenes. At the RNA level, antisense
techniques prevent transport and translation of the oncogene mRNA by providing
a complementary RNA molecule (e.g., C-myc gene). Ribozymes, antisense
oligonucleotides with a cleavage action will reduce the stability of oncogene
mRNA. Restoration of the tumour suppressor gene such as p53 can be sufficient
to cause cellular apoptosis and arrest tumour growth.
Molecular chemotherapy for cancer cells
Herpes
simplex virus thymidine kinase (HSV-Tk) converts the prodrug ganciclovir into
toxic metabolites. This toxicity is sufficient enough to kill the cancer cells.
DNA repair by gene therapy
Another
approach involves the repairing of a gene using chimeric oligonucleotides.
Homologous recombination is a natural process that controls the replacement of
a defective gene. Highly precise DNA repair is performed by using DNA
oligonucleotides to introduce site specific changes in the genome, even a
single incorrect base can be corrected.
Transplantation tolerance in organ transplanted patients
In organ transplanted
patients, the use of immunosuppressive drug is associated with increased risk
of the development of cancer, infectious and ischemic heart disease. Gene
therapy can be used to reduce the immunogenicity by introduction of genes to
block T-cell activation.
HIV treatment by gene therapy
By
introducing an antiviral gene into an infected T-lymphocyte, the HIV virus can
be killed or expressing an antiviral gene in the normal T-lymphocyte may
protect the patient from future HIV infection.
Replacement of hormones and blood factors by gene therapy
If an
erythropoietin gene or factor IX gene is transferred via adeno-associated
vector into muscles, it will cause the expression of relevant protein.
Prodrug activation
In herpes
simplex virus thymidine kinase method, the thymidine kinase enzyme in every
transduced cell converts the prodrug ganciclovir into monophosphate and triphosphates
forms. The triphosphate form of ganciclovir interferes with the DNA replication
and kill the cancer cells.
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