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Targeting DNA

Targeting DNA. Project of principles of Genetics Dr.Mashayekhan. 90103044 90102886 90103593. Alireza Delfarah Mojtaba Talafi Shayan Morshedi. CONTENTS. Preface and history Methods of targeting DNA Limits and problems Future and targeting DNA Conclusion References. Targeting DNA.

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Targeting DNA

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  1. Targeting DNA Project of principles of Genetics Dr.Mashayekhan 90103044 90102886 90103593 AlirezaDelfarah MojtabaTalafi ShayanMorshedi

  2. CONTENTS • Preface and history • Methods of targeting DNA • Limits and problems • Future and targeting DNA • Conclusion • References Targeting DNA

  3. Targeting DNA • Replacing or supplementing a mutated gene with a new, accurate copy, • Treat and cure countless human genetic diseases, • Finding the appropriate delivery vector to target the diseased tissues in the body, while avoiding unintended consequences has challenged therapists. Targeting DNA

  4. Most common form of gene therapy • 1. Using DNA that encodes a functional, therapeutic gene to replace a mutated gene, • 2. Directly correcting a mutation, • 3. Using DNA that encodes a therapeutic protein drug to provide treatment. • DNA is packaged within a “vector”, which is used to get the DNA inside cells within the body. Targeting DNA

  5. A brief history of gen therapy • First conceptualized in 1972. • The first gene therapy clinic was established in 1989, rising to 116 in 1999. • The first FDA-approved gene therapy experiment in the US occurred in 1990. Targeting DNA

  6. In 1999 a relatively 18-year-old who had a mild form of liver disease caused by mutations, died 4 days after receiving an injection of an adenovirus. • In 2002, clinical trials for treatment of a leukemia-like disease called severe combined immunodeficiency (SCID), were hailed as the first unequivocal gene therapy success. Events like this had a big negative impact in the field. • But things are looking up, for example: two years ago, researchers published long-term survival data for two UK gene therapy trials for SCID. Targeting DNA

  7. DELIVERING NEW GENES Gene targeting has been widely used to study human genetic diseases by removing ("knocking out"), or adding ("knocking in"), specific mutations of interest to a variety of models. Targeting DNA

  8. The two major classes of gene therapy methods Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by a number of methods. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods). • Viral methods • Non-viral methods Targeting DNA

  9. Viral methods • All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Therefore this has been recognized as a plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA. • A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex virus, vaccinia, pox virus and adeno-associated virus. Targeting DNA

  10. Common viruses used for gene therapies • Nonintegrating Viruses • Integrating Viruses • Oncolytic Viruses Targeting DNA

  11. Targeting DNA

  12. A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein. Targeting DNA

  13. Targeting DNA

  14. Nowadays • Many other gene therapy trials are currently underway for many diseases including various forms of hereditary blindness, HIV, hemophilia, neurodegenerative diseases, and a variety of cancers. • Nearly 2000 clinical trials were initiated between 2007-2012. • Many with miraculous results and none of the devastating side effects that plagued the field in its early days. Targeting DNA

  15. Limits and problems • The cost and expense of targeting DNA. • The unwanted mutation which may happen instead of what we want. • The problem of treatment in the not-prepared societies. • Limited sizes in some cases. Targeting DNA

  16. In the future • Clearly gene therapy is going to be a therapeutic pathway forward for a whole range of diseases. • it may be that every individual’s cancer genome will be sequenced. This would better define which defective DNA repair pathways to target using the synthetic lethality approach. Targeting DNA

  17. Once such defective pathways are defined for all tumor types, drug development can target the alternative, required pathway. • this information can be used as a biomarker to predict response to these agents. Thus, targeting DNA repair to enhance cancer therapy is one of the most innovative advances in cancer drug development in the last decade and may become widely applied in many areas of oncology. Targeting DNA

  18. Conclusion…

  19. References • H.B. Gaspar et al., “Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency,” SciTransl Med, 3:97ra79, 2011. • H.B. Gaspar et al., “Hematopoietic stem cell gene therapy for adenosine deaminase–deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction,” SciTransl Med, 3:97ra80, 2011. • A.C. Nathwani et al., “Adenovirus-associated virus vector-mediated gene transfer in hemophilia B,” N Engl J Med, 365:2357-65, 2011. • S.G. Jacobson et al., “Gene therapy for Leber congenital amaurosis caused by RPE65 mutations,” Arch Ophthalmol, 130:9-24, 2012. • H.L. Kaufman et al., “Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma,” Annals of Surgical Oncology, 17:718-30, 2010. • X.M. Xie et al., “Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models,” Cancer Cell, 12:52-65, 2007. • J.-Y. Lang, “BikDD eliminates breast cancer initiating cells and synergizes with lapatinib for breast cancer treatment,” Cancer Cell, 20:341-56, 2011. • D.L. Porter et al., “Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia,” N Engl J Med, 365:725-33, 2011. • M. Kalos et al., “T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia,” SciTransl Med, 3:95ra73, 2011. • G. Hütter et al., “Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation,”NEngl J Med, 360:692-98, 2009. Targeting DNA

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