EXPLAINS GENE THERAPY SUCESS..

1. LOGO
Success of gene
therapy
by- Nitin Kshirsagar

2. Outline
Introduction to gene therapy
Global gene therapy market
Significance in therapeutics
Success of gene therapy
Current scenario
Challenges

3.  ―It's a history book - a narrative of the journey of our
species through time. It's a shop manual, with an
incredibly detailed blueprint for building every
human cell.
 It's a transformative textbook of medicine, with
insights that will give health care providers immense
new powers to treat, prevent and cure disease."
- Francis Collins
Introduction to Gene Therapy
I. Genome = approx. 3 billion base pairs
II. One base pair is 0.00000000034 meters
III. DNA sequence in any two people is 99.9% identical – only
0.1% is unique!

4. Genetic disorders
 Single gene disorders caused by a mistake in
a single gene. Sickle cell, cystic fibrosis and
Tay-Sachs
 Chromosome disorders caused by an excess
or deficiency of the genes. Down syndrome is
caused by an extra copy of a chromosome
(but no individual gene on the chromosome is
abnormal)
 Multifactorial inheritance disorders caused by
a combination of small variations in genes,
most cancers, Alzheimer's.

5. Gene therapy
 In 1865 Mendel’s observations led to laws regarding
the transmission of hereditary characteristics from
generation to generation
 1940s - Avery and colleagues
 1953 –Watson and Crick
 1990 - The first gene therapy journal published,
Human Gene Therapy
 1990 - Ashanthi DeSilva, ADA-deficient Severe
Combined Immunodeficiency
 2000 - The first cure Alain Fischer (Paris) totally
correcting children with SCID-X1

6. Global gene therapy market

7.  The once abandoned gene therapy field has become a hotbed, with 11
different companies raising at least $618 million from venture capitalists
and the public markets since the beginning of 2013, and one more, AGTC
(Australasian Gene Therapy Society) plans a $50 million initial
public offering soon. The iShares Nasdaq Biotechnology Index is up 65%
in 12 months.
 In March 2014 researchers at the University of Pennsylvania reported that
12 patients with HIV had been treated since 2009 in a trial with a
genetically engineered virus with a rare mutation known to protect against
HIV (CCR5 deficiency) top talent is being attracted to what was once seen
as a lost cause
 Cedars-Sinai Regenerative Medicine Institute has received a $2.5 million
grant from the Department of Defense to conduct animal studies that, if
successful, could provide the basis for a clinical trial of a gene
therapy product for patients with Lou Gehrig's disease, also called
amyotrophic lateral sclerosis(ability to initiate and control muscle
movement is lost.)-
News medical, BBC 31.3.13

8. Significance in therapeutics

9. Means of gene therapy
 Viruses- adenoviruses, retro viruses (unlike Ad, transfect by integrating the transgene
into the target-cell chromosome)
 Naked gene transfer- to elucidate mechanisms of gene expression and the
role of genes and their cognate proteins in the pathogenesis of disease in
animal models also being used in several human clinical trials like- genetic
vaccines, Duchenne muscular dystrophy, peripheral limb ischemia, cardiac
ischemia
 Needle-free injection- gene gun, Intraject or Jetgun
 Electroporation - involves the application of a pulsed electric field enhance
cell permeability, resulting in the transit of exogenous polynucleotide
across the cytoplasmic membrane performed by locally injecting DNA to
the site of interest followed by the application of electric field
local injection < systemic injection
 Condensed DNA particles- polymers are heterogeneous polylysine,
polyethylene imine
 Liposomes
Burdette, Walter J. The Basis for Gene Therapy. Springfield: 2001

10. Path towards successful GT

11. Success of gene therapy
GT drugs as Anti-cancer
The increasing popularity of cancer therapeutics as a major interest for
gene therapy applications led to it accounting for a dominant share of more
than 60% in the overall number of clinical studies
Rexin-G A tumor-targeted retrovector bearing a cytocidal cyclin G1 construct,
is the first targeted gene therapy vector to gain fast track designation and
orphan drug priorities for multiple cancer indications in US
Gendicin Recombinant Ad-p53 gene therapy for head and neck squamous cell
carcinoma (HNSCC)—a cancer that accounts for about 10% of the 2.5
million annual new cancer patients in China.
The reasons for cancer to become a preferred area of application for gene
therapy are the significant unmet medical needs in cancer therapy, coupled
with the large size of its market. Additionally, the ethical acceptance of
gene therapy as a therapeutic solution also a contribution

12. CVS
 Stem cell transplantation therapies that would accelerate
natural processes of postnatal collateral vessel formation, an
approach referred to as therapeutic angiogenesis
 Coronary (CAD) and peripheral (PAD) artery disease
 Direct intramyocardial injection of VEGF DNA using an
adenovirus vector in patients with otherwise inoperable
coronary artery disease and intractable angina pectoris
Rhumatoid arthritis- liposome, plasmid, RNAi
Alpha-1 antitrypsin (AAT) deficiency -is a hereditary disorder
associated with mutations in the SERPINA1 gene

13.  Over 100 different alleles have been identified however the most common
disease-causing mutation
Others:-

14. RNA interference
 RNA interference, also known as RNAi presents a new
approach to gene therapy by targeting specific genes and
down-regulating gene expression
 One of the most potent forms of RNAi is small interfering
RNA, or siRNA
 Small fragments of double stranded RNA, specific for a
particular gene target, are introduced to the cell
 Specific hybridization between the naturally occurring
transcript and the induced siRNA (antisense portion)
instigates the destruction of the message.
 directly on the transcriptional level of gene expression.
 Therapeutically speaking, siRNA efficacy would be
determined by percent knock-down
 BUT- this method is transient, requiring re-administration

15. Current scenario
The most promising gene-therapy concepts, at the
present time :
1. Direct killing of tumour cells with genes delivered by
Ad vectors for local management of cancer;
2. Delivery of naked DNA by injection or by the gene
gun for preventative vaccination against infectious
diseases;
3. Naked DNA delivery of genes promoting
angiogenesis for cardiovascular disorders; and
4. AV delivery for chronic disorders, such as
haemophilia and anaemia

16. Challenges
 Short Lived- Hard to rapidly integrate therapeutic
DNA into genome and rapidly dividing nature of cells
prevent gene therapy for long time
 Immune Response- leads to immune response
Increased response when a repeat offender enters
 Viral Vectors- patient could have toxic, immune,
inflammatory response
also may cause disease once inside
 Multigene Disorders- Heart disease, high blood
pressure, Alzheimer’s, arthritis diabetes,etc. need to
introduce more than one gene
 May induce a tumor if integrated in a tumor
suppressor gene because of insertional mutagenesis
 Ethical and moral challenges

17. Thankk you…