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THERAPIES FOR
GENETIC DISEASES
SUBMITTED BY –
Farheen Khan
Roll no –19MBS007
MSc. Biosciences
1st year (2nd semester)
GENE THERAPY
There are two basic approaches to gene therapy: germline therapy and
somatic cell therapy.
Germ line gene therapy is where germ cells (sperm or egg) are
modified by the introduction of functional genes, which are integrated
into their genome. Therefore changes due to therapy would be heritable
and would be passed on to later generation.Germline therapy is usually
carried out by microinjection of a somatic cell followed by nuclear
transfer into an oocyte, and theoretically could be used to treat any
inherited disease.
Somatic cell therapy involves manipulation of cells, which either can
be removed from the organism, transfected, and then placed back in the
body, or transfected in situ without removal. The technique has most
promise for inherited blood diseases (e.g., hemophilia and
thalassaemia), with genes being introduced into stem cells from the
bone marrow, which give rise to all the specialized cell types in the
blood. The strategy is to prepare a bone extract containing several
billion cells, transfect these with a retrovirus-based vector, and then re-
implant the cells. Subsequent replication and differentiation of
transfectants leads to the added gene being present in all the mature
blood cells.Somatic cell therapy also has potential in the treatment of
lung diseases such as cystic fibrosis, as DNA cloned in adenovirus
vectors or contained in liposomes is taken up by the epithelial cells in
the lungs after introduction into the respiratory tract via an inhaler.
Gene therapy states and remains an experimental discipline and many
researches remain to be performed before the treatment will realize its
potential. Majority of the gene therapy trials are being conducted in
united States and europe, with only a modest number in other countries
including Australia. Scope of this approach is broad with potential in
treatment of diseases caused by single gene recessive disorders (like
cystic fibrosis, hemophilia, muscular dystrophy, sickle cell anemia
etc), acquired genetic diseases such as cancer and certain viral infections
like AIDS.
CANCER
The first FDA-approved gene therapy experiment in the United States
occurred in 1990 for a patient with severe combined immunodeficiency
disorder. Since then, many clinical trials have been conducted for
patients with cancer, using different approaches in gene therapy, with
successful results reported in patients with chronic lymphocytic
leukemia, acute lymphocytic leukemia, brain tumors, as well as others.
Several commercially approved medications for gene therapy were
released, including ONYX-15 (Onyx Pharmaceuticals) for refractory
head and neck cancer , human papilloma virus vaccine for the
prevention of cancer cervix (2006) and modified dendritic cells,
sipuleucel-T, for minimally symptomatic, castration-resistant metastatic
prostate cancer .
Most cancers result from activation of an oncogene that leads to tumor
formation, or inactivation of a gene that normally suppresses formation
of a tumor. In both cases a gene therapy could be envisaged to treat the
cancer. Inactivation of a tumor suppressor gene could be reversed by
introduction of the correct version of the gene by one of the methods
described above for inherited disease. Inactivation of an oncogene
would, however, require a more subtle approach, as the objective would
be to prevent expression of the oncogene, not to replace it with a non-
defective copy . One possible way of doing this would be to introduce
into a tumor a gene specifying an antisense version of the mRNA
transcribed from the oncogene. An alternative would be to introduce a
gene that selectively kills cancer cells or promotes their destruction by
drugs administered in a conventional fashion. This is called suicide
gene therapy and is looked on as an effective general approach to
cancer treatment, because it does not require a detailed understanding of
the genetic basis of the particular disease being treated. Many genes that
code for toxic proteins are known, and there are also examples of
enzymes that convert non-toxic precursors of drugs into the toxic form.
Introduction of the gene for one of these toxic proteins or enzymes into
a tumor should result in the death of the cancer cells, either immediately
or after drug administration .
Another approach is to use gene therapy to improve the natural killing
of cancer cells by the patient’s immune system, perhaps with a gene that
causes the tumor cells to synthesize strong antigens that are efficiently
recognized by the immune system. All of these approaches, and many
not based on gene therapy, are currently being tested in the fight against
cancer.
In trials using a type of virus known as adenovirus, viral therapy has
shown encouraging results against several types of cancers, including
squamous cell cancers of the head and neck, and is being tested as a
preventive treatment for precancerous oral tissue. Trials involving
modified forms of herpes simplex virus have been conducted in patients
with malignant glioma (a form of brain cancer) and colorectal cancer
that has spread to the liver.
CAR T-cell therapy, which seeks to enhance the natural cancer-
fighting ability of patients’ own T cells, is one type of immunotherapy.
A sample of a patient’s T cells is collected and mixed with viruses
carrying several specific genes. The viruses deliver these genes to the T
cells’ nuclei, where they’re incorporated into the cells’ DNA. The genes
cause the T cells to express a special protein called a chimeric antigen
receptor, or CAR, on their surface. The CAR directs the T cell to the
tumor cell using a specific “address,” and the CAR T cell is then
equipped to rapidly destroy the cancer cell. When the cells, now called
CAR T cells, are infused into the patient, they seek out tumor cells and
then proliferate to generate many more cancer-killing cells.
Another form of immunotherapy involving gene therapy is cancer
vaccines. This approach involves collecting tumor cells from a patient
and engineering them with genes that cause them to be more
conspicuous to the immune system. The altered cells are then re-infused
into the patient along with an immune-stimulating compound. The
patient’s immune system launches a vigorous attack not only on the
newly-infused cancer cells but also on similar cells throughout the body.
SICKLE CELL ANEMIA
Sickle cell anemia is caused by a mutation in the HBB gene which
provides the instructions to make part of hemoglobin, the protein in red
blood cells that carries oxygen. Researchers are working on two
different strategies to treat sickle cell anemia with gene therapy. Both of
these strategies involve genetically altering the patient’s
own hematopoietic stem cells. These are cells in the bone marrow that
divide and specialize to produce different types of blood cells, including
MUSCULAR DYSTROPHY
Muscular dystrophy refers to a group of more than 30 inherited diseases
that result in progressive weakening and wasting of muscles. These
diseases are caused by mutations in genes that are involved in the
production of proteins required for muscles to work properly.
Currently, several kinds of gene therapies are being investigated to treat
muscular dystrophy, and possibly offer the chance of a cure. These
approaches are summarized below.
Exons are part of the gene that provides instructions to produce a
working protein. Exon skipping is the “patching” of that part of the
gene with missing or mutated exons, using short stretches of DNA
called antisense oligonucleotides (AO). This can lead to the production
of a truncated, albeit functional, protein to ease some of
the symptoms of muscular dystrophy. Exon skipping is currently
being evaluated in clinical trials for Duchenne muscular dystrophy
(DMD) and Becker muscular dystrophy (BMD) as these disorders are
caused due to deletion of exons at several places in the DMD gene.
Alternative strategy involves over-expression of compensating genes
either through gene transfer or by up regulating expression using
small molecules. Utrophin the paralog of dystrophin is highly
expressed in the fetal period. Over expression of utrophin, confers a
protective effect.. Encouraging result like improved muscle function
are obtained in mice with dystrophin deficiency when utrophin
transgenes are over expressed. Now researchers are trying to
discover new molecule which can upregulate the utrophin gene
expression upon administration.
REFERENCES
GENE CLONING AND DNA ANALYSIS An
Introduction T.A. BROWN Sixth Edition
https://en.m.wikipedia.org/wiki/Gene_therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC157048
7/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC476008
9/