Credits 3.2, 3.3, 3.

5
GENE THERAPY

 Genetic disorders - progressive disability,

chronic ill health; no effective cure as on date.
Conventional methods of treatment cannot
cure genetic diseases.
If no knowledge of the underlying cause / no
understanding of the molecular basis of the
disease - no cure
If this is understood then dietary restriction,
as in phenylketonuria, or hormone
replacement, as in congenital adrenal
hyperplasia can be used very successfully in
the treatment of the disorder

 The understanding of genetic disease at a

molecular level is the foundation of
rational therapy.
The objective in treating genetic disease is
to eliminate or ameliorate the effects of
the disorder, not only on the patient but
also on his or her family.
Various strategies for management of
genetic diseases - diet, protein/ enzyme/
metabolite replacement, small molecule
treatment [skipping over mutant codons]

 Advances in molecular biology leading

to the identification of many important
human disease genes and their protein
products have raised the prospect of
gene therapy for many genetic
disorders.
The first human gene therapy trial
began in 1990, but, progress to date
has been limited and there are many
practical difficulties to overcome before
gene therapy can deliver its promise.

 Gene therapy has been defined by the UK Gene

Therapy Advisory Committee (GTAC) as 'the
deliberate introduction of genetic material into
human somatic cells for therapeutic,
prophylactic or diagnostic purposes'.
It includes techniques such as
Delivery of synthetic or recombinant nucleic acids into
humans;
genetically modified biological vectors ( such as viruses or
plasmids), nucleic acids associated with delivery vehicles
naked nucleic acids
antisense techniques (DNA or RNA technologies such as RNA
interference eg. gene silencing, gene correction or gene
modification)
genetic vaccines
genetically modified stem cells
xenotransplantation of animal cells (but not solid organs).

 Gene therapy---any procedure

intended to treat or alleviate disease
by genetically modifying the cells of a
patient [or]
introduction of normal genes into cells
in place of defective or missing ones in
order to correct genetic disorders.
Material transferred into patient cells can be
genes
gene segments
Oligonucleotides

 Based on mode of delivery of therapeutic

gene into the patients cells
Ex vivo gene therapy---cells are removed from
the patient and the genetic material inserted into
them in vitro, prior to transplanting the modified
cells back into the patient
In vivo gene therapy---genetic material is
transferred directly into cells within a patient

Depending on the molecular basis of the

disease---gene therapy procedure is decided.

 Based on function of introduced gene-- Classical gene therapy----The rationale of this

type of approach is to deliver genes to appropriate
target cells with the aim of obtaining optimal
expression of the introduced genes. Once inside
the desired cells in the patient, the expressed genes
are intended to do one of the following:
produce a product that the patient lacks;
kill diseased cells directly, e.g. by producing a toxin which
kills the cells;
activate cells of the immune system so as to aid killing of
diseased cells.

Nonclassical gene therapy----the delivered DNA

sequence inhibits the expression of genes
associated with the pathogenesis, or to correct a
genetic defect and so restore normal gene
expression.

 Based on cells that are used for

modification-----somatic gene
therapy and germline gene therapy.
Current gene therapy is exclusively
somatic gene therapy, the
introduction of genes into somatic
cells of an affected individual. The
prospect of human germline gene
therapy raises a number of ethical
concerns, and is currently not
sanctioned

Importance of gene therapy

Gene therapy is helpful in developing
novel treaments for diseases for
which there is no effective
conventional treatment.
Gene therapy has the potential to
treat all of the several kinds of
disorders. Depending on the basis of
pathogenesis, different gene therapy
strategies can be considered

 Infectious diseases (as a result of infection by a

virus or bacterial pathogen)
Cancers (inappropriate continuation of cell
division and cell proliferation as a result of
activation of an oncogene or inactivation of a
tumor suppressor gene or an apoptosis gene)
Inherited disorders (genetic deficiency of an
individual gene product or genetically
determined inappropriate expression of a gene);
Immune system disorders (includes allergies,
inflammations and also autoimmune diseases, in
which body cells are inappropriately destroyed by
immune system cells).

 Immune system-mediated cell killing. In many gene

therapies the target cells are healthy immune system cells,
and the idea is to enhance immune responses to cancer
cells or infectious agents (Section 22.5.1).
Delivery of gene products from cells at a remote location.
Genes may be targeted initially to one type of tissue while
the gene products may be delivered to a remote location.
For example, the myonuclei in muscle fibers have the
advantage of being very long lived. Genetically engineered
myoblasts therefore have the potential to ameliorate some
nonmuscle diseases through long-term expression of
exogenous genes which encode a product secreted into the
blood stream (see for example, Jiao et al., 1993).