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Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
Success of gene therapy
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Success of gene therapy

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EXPLAINS GENE THERAPY SUCESS..

EXPLAINS GENE THERAPY SUCESS..

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  • Genes are carried on chromosomes and are the basic physical and functional units of heredity Genes are specific sequences of bases that encode instructions on how to make proteins When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders result
  • characteristics: (1) a high capacity for self-renewal; (2) the potential for differentiation in multiple cell types; (3) the ability to be cultured ex vivo and used for tissue engineering; and (4) plasticity (transdifferentiation ability) (Vats et al., 2005). On the basis of their differentiating potential, stem cells can currently be classified into four categories: (1) totipotent, (2) pluripotent, (3) multipotent, and (4) oligopotent or monopotent. Totipotent stem cells have the potential to differentiate into cells of all three main germinal layers (the ectodermal, endodermal, and mesodermal) and embryo-derived tissues. Pluripotent stem cells have the ability to differentiate only into tissues derived from the ectoderm, endoderm and mesoderm. Multipotent stem cells can differentiate into tissue-specific progenitor cells within a given organ. For example, multipotent blood stem cell or hematopoietic stem cells can develop into red blood cells, white blood cells, or platelets. Oligopotent or monopotent stem cells can only give rise to one or few types of specialized cells. On the basis of their origin and biological properties, stem cells can also be classified as either (1) embryonic stem cells or (2) adult stem cells. Embryonic stem cells are derived from the inner layer mass of the blastocyst and can be harvested from three sources: aborted fetuses (cadaveric stem cells), embryos left over from in vitrofertilization (discarded embryos), and embryos created in the laboratory solely for the purpose of producing stem cells (research embryos). In vitro differentiation of human embryonic stem cells into cardiomyocytes has been demonstrated by Kehat et al. (Kehat et al., 2001). However, ethical issues have been raised against harvesting human embryonic stem cells, especially if this process requires destruction of an embryo. Other potential obstacles to using embryonic stem cells are that recipients often need to receive immunosuppressants, because embryonic stem cells are potentially allogenic and strongly immunogenic. Uncontrolled differentiation of embryonic stem cells may cause other problems, such as the development of cardiac or vascular neoplasm. Transplanted embryonic stem cells may form teratomas if some undifferentiated totipotent cells are still present. The formation of teratomas -i.e., tumors containing a mix of differentiated human cell types, including cells characteristic of the ectoderm, mesoderm, and endoderm-in severe combined immunodeficiency (SCID) mice after injection with human embryonic stem cells has been observed (Thomson et al., 1998). Adult stem cells are the undifferentiated cells that exist in a differentiated tissue or organ and that are capable of specializing into cells of the tissue or organ from which they originated. Their capacity for self-renewal allows tissues and organs to maintain functional stability. Sources of adult stem cells include not only regenerating tissues, such as the heart, adipose tissue, bone marrow, blood, liver;;’’’RNA interference (RNAi) is known to be a powerful means of sequence-specific gene silencing and would thus be a good candidate for this new strategy. RNAi was first reported in 1998 by Fire et al. who demonstrated that double-stranded RNA induced sequence-specific silencing of gene expression in nematode cells (
  • Hugocalled Human Gene Therapy Subcommittee, or HGTS n nih
  • Transcript

    • 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…

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