1. RECENT ADVANCES
IN GENE THERAPY
- Purvi Shah

2. Gene therapy is an experimental technique that uses genes to treat or prevent
disease. In the future, this technique may allow doctors to treat a disorder by
inserting a gene into a patients cells instead of using drugs or surgery.
Gene therapy was first conceptualized in 1972
Researchers are testing several approaches to gene therapy, including:
Replacing a mutated gene that causes disease with a healthy copy of the
gene.
Inactivating, or “knocking out,” a mutated gene that is functioning
improperly.
Introducing a new gene into the body to help fight a disease.
What Is Gene Therapy

3. Although early clinical failures led many to dismiss gene therapy as
over-hyped, clinical successes since 2006 have bolstered new optimism
in the promise of gene therapy.
These include successful treatment of patients with the retinal
disease, X-linked SCID, adrenoleukodystrophy, chronic lymphocytic
leukemia(CLL), acute lymphocytic leukemia(ALL), multiple
myeloma and Parkinson's disease.
These recent clinical successes have led to a renewed interest in gene
therapy, with several articles in scientific and popular publications
calling for continued investment in the field.

4. Types Of Gene Therapy
Gene therapy may be classified into two types:
1. Somatic gene therapy - the therapeutic genes are
transferred into the somatic cells, or body, of a patient. Any
modifications and effects will be restricted to the individual
patient only, and will not be inherited by the patient's
offspring or later generations
2. Germ line gene therapy - sperm or eggs, are modified by
the introduction of functional genes, which are integrated
into their genomes. This would allow the therapy to be
heritable and passed on to later generations

7. Gene Therapy Depends on
Delivery of Corrective Genes
Viral vectors are a tool commonly used by molecular
biologists to deliver genetic material into cells.
This process can be performed inside a living
organism (in vivo) or in cell culture (in vitro).
Viruses have evolved specialized molecular
mechanisms to efficiently transport their genomes
inside the cells they infect

8. Viruses are used as Delivery
Tolls
Viruses are used as vectors to introduce the genetic
material inside the bodies.
These viruses are inactivated, they are not able to
reproduce
1. Adenoviruses
2. Herpes viruses - DNA tumor viruses
3. Retroviruses - RNA tumor viruses

10. First Approved Gene Therapy
On September 14, 1990 at the U.S. National Institutes of Health, W. French
Anderson M.D. and his colleagues R. Michael Blaese, M.D., C. Bouzaid, M.D., and
Kenneth Culver, M.D., performed the first approved gene therapy procedure on
four-year old Ashanthi DeSilva, Born with a rare genetic disease called severe
combined immunodeficiency (SCID)
What did they do
In Ashanthi's gene therapy procedure, doctors removed white blood cells from the
child's body, let the cells grow in the laboratory, inserted the missing gene into the
cells, and then infused the genetically modified blood cells back into the patient's
bloodstream.

12. A success story
As of early 2007, she was still in good health, and
she was attending college. Some would state that the
study is of great importance despite its indefinite
results, if only because it demonstrated that gene
therapy could be practically attempted without
adverse consequences

13. 'mending broken hearts' by using gene
therapy
Novel techniques to “mend broken hearts” using gene therapy and stem cells
represent a major new frontier in the treatment of heart disease
It was achieved by the researchers at Gladstone Institute of Cardiovascular Disease in
California
They were able to re-programme scar-forming cells into heart muscle cells, some of
which were capable of transmitting the kind of electrical signals that make the heart beat
They performed on a live mice, transforming scar-forming cells, called fibroblasts,
into beating heart muscle cells
They injected three genes (cocktail of genes) into the heart of live mice that had been
damaged by heart attack, fibroblasts could be turned into working heart cells.
Researchers said that the “cocktail of genes” used to regenerate cells could one day be
replaced with “small drug-like molecules” that would offer safer and easier delivery

14. First Real-Time MRI-Guided Gene Therapy for Brain
Cancer
Neurosurgeons at the University of California, San Diego School of Medicine and UC San
Diego Moores Cancer Center are among the first in the world to utilize real-time magnetic
resonance imaging (MRI) guidance for delivery of gene therapy as a potential treatment for
brain tumors
Using MRI navigational technology, neurosurgeons can inject Toca 511 (vocimagene
amiretrorepvec), a novel investigational gene therapy, directly into a brain malignancy
The new approach offers a precise way to deliver a therapeutic virus designed to make the
tumor susceptible to cancer-killing drugs

15. Toca 511 is a retrovirus engineered to
selectively replicate in cancer cells, such as
glioblastomas.
Toca 511 produces an enzyme that converts
an anti-fungal drug, flucytosine (5-FC), into
the anti-cancer drug 5-fluorouracil (5-FU).
After the injection of Toca 511, the patients
are treated with an investigational extended-
release oral formulation of 5-FC called Toca
FC.
Cancer cell killing takes place when 5-FC
comes into contact with cells infected with
Toca 511.

16. UCLA researchers combine cellular
and gene therapies to develop
treatment for breast cancer
Carol Kruse, a professor of neurosurgery and member of the Jonsson Cancer Center
and the UCLA Brain Research Institute led the research on breast cancer
Breast cancer is the most common form of cancer in women, and metastasis is a major
cause of health deterioration and death from the disease
Cellular therapy and gene therapy were used together to treat breast cancer
Cellular therapy is a type of immunotherapy that uses T cells, the foot soldiers of
the immune system, that have been sensitized in the laboratory to kill breast cancer
cells.
These sensitized T cells are injected into the parts of the brain to which cancer
has spread.
The research shows that the T cells can move through tissue and recognize and
directly kill the tumor cells

17. stem cell gene therapy gives hope to
prevent inherited neurological disease
Scientists from The University of Manchester have used stem cell gene
therapy to treat a fatal genetic brain disease
It was used to treat Sanfilippo – a fatal inherited condition which causes
progressive dementia in children
Sanfilippo, is currently untreatable mucopolysaccharide (MPS) disease
It is caused by the lack of SGSH enzyme in the body which helps to breakdown
and recycle long chain sugars, such as heparan sulphate (HS)
Children with the condition build up and store excess HS throughout their body
from birth which affects their brain and results in progressive dementia and
hyperactivity, followed by losing the ability to walk and swallow

18. Researchers have developed a stem cell gene therapy which overproduces
the SGSH enzyme specifically in bone marrow white blood cells to increase
SGSH enzyme from bone marrow transplants, and to target it to the cells that
traffic into the brain
It was seen that mice treated by this method produce five times the normal
SGSH enzyme levels in the bone marrow and and 11 per cent of normal levels
in the brain
The enzyme is taken up by affected brain cells and is enough to correct
brain HS storage and neuro inflammation to near normal levels and
completely corrects the hyperactive behaviour in mice with Sanfilippo

19. Mucopolysaccharidosis Type IIIA
potential gene therapy
Mucopolysaccharidosis Type IIIA (MPSIIIA) is a metabolic disorder in which the body
is missing an enzyme that is required to break down long chains of sugars known as
glycosaminoglycans
The glycosaminoglycans collect in the body and cause damage, particularly in the
brain if not broken
Fàtima Bosch and colleagues at Universitat Autònoma de Barcelona in Spain
developed a form of gene therapy to replace the enzyme that is missing in MPSIIIA
They injected the replacement gene into the cerebrospinal fluid that surrounds the brain
and spinal cord
This study demonstrates that gene therapy can be delivered to the brain through the
cerebrospinal fluid and suggests that this approach could potentially be used as a therapy
for MPSIIIA

22. IS GENE THERAPY TOTALLY SAFE ??
Although gene therapy is a promising treatment
option for a number of diseases (including inherited
disorders, some types of cancer, and certain viral
infections), the technique remains risky and is still
under study to make sure that it will be safe and
effective.
Gene therapy is currently only being tested for the
treatment of diseases that have no other cures

23. Technical Difficulties in Gene
Therapy
Gene delivery: Successful gene delivery is not easy or
predictable, even in single-gene disorders.
For example, although the genetic basis of cystic fibrosis is well
known, the presence of mucus in the lungs makes it physically
difficult to deliver genes to the target lung cells.
Delivery of genes for cancer therapy may also be complicated
by the disease being present at several sites.
Gene-therapy trials for X-linked severe combined
immunodeficiency (X-SCID), however, have been more
successful

24. Problems with Gene Therapy
Short Lived
Hard to rapidly integrate therapeutic DNA into genome and rapidly dividing nature
of cells prevent gene therapy from long time
Would have to have multiple rounds of therapy
Immune Response
new things introduced leads to immune response
increased response when a repeat offender enters
the gene might be over-expressed (toxicity)
Viral Vectors
patient could have toxic, immune, inflammatory response
also may cause disease once inside

25. Multigene Disorders
Heart disease, high blood pressure, Alzheimer’s, arthritis and diabetes are hard to
treat because you need to introduce more than one gene

26. Do not forget
Genes can be
Unpredictable
?