Targeted gene therapy

TARGETED GENE THERAPHY

1. TARGETED GENE THERAPY DR.S.SELVA MANI II YEAR POST GRADUATE DEPT.OF.PUBLIC HEALTH DENTISTRY

2. CONTENTS Introduction Gene therapy Historical background Types of gene therapy Steps in gene therapy Various Vector agents Route of administration Cancer –gene theraphy Hallmarks of tumor Conclusion

3. INTRODUCTION

4. GENE THERAPY ?

5. HISTORY Ashanti DeSilva Jesse Gelsinger

6. TYPES GERM LINE THERAPY 2. SOMATIC GENE THERAPY EX –VIVO GENE THERAPY IN -VIVO GENE THERAPY

7. EX-VIVO GENE THERPHAY

8. EX-VIVO GENE THERPHAY

9. IN –VIVO GENE THERPHAY

10. IN –VIVO GENE THERPHAY

11. IN –VIVO GENE THERPHAY

12. STEPS IN GENE THERAPY

13. METHODS In vivo approach- Inject the vector into the body and specifically target affected cells . Ex vivo approach- Isolating the desired cells from the body. Culturing the cells in a Petri dish in the laboratory.

14. IDEAL CHARACATERISTICS OF VECTOR VARIOUS TYPES OF VECTOR

15. MICROMANIPULATOR .

16. ROUTE OF ADMINISTRATION

17. Immuno-gene therapy chemoprotection s uicide gene therapy t umor suppressor (p53)

18. Cancer gene therapy Direct attack on tumor cells transfer of tumor suppressor gene inhibition of oncogenes suicide genes oncolytic viruses (replication-competent viruses) Harnessing immune response to tumor antigens Chemoprotection Anti-angiogenic therapy

19. p53 – the guardian of the genome

20. p53-induced cell-cycle arrest in response to DNA damage. The normally unstable p53 protein is stabilized by damaged DNA, so its concentration increases. Acting as a transcription factor, p53 induces expression of p21 CIP , a cyclin-kinase inhibitor that inhibits all Cdk1-, Cdk2-, Cdk4-, and Cdk6- cyclin complexes. Binding of p21 CIP to these Cdk-cyclin complexes leads to cell cycle arrest in G 1 and G 2

21. First officially registered therapeutic nucleic acid Gendicine (SiBiono GeneTech, Chiny ) Adenoviral vector with a correct p53 gene Efficient in patients with head and neck cancers Appears 3 x more efficient than radiotherapy alone Registered on 16. X. 2003, after 5 years of clinical trials

22. Advexin – adenoviral vector expressing p53 gene effective in patients with head and neck cancer

23. Nature Biotechnology, January 2004 Examples of the most advanced clinical trials of cancer gene therapy

24. Suicide gene therapy –pro-drug activation The objective of pro-drug activation therapy is to express an activating enzyme within the tumor, which will then activate a systemically delivered, inactive pro-drug at the target site only

25. Enzyme-prodrug combination for suicide gene therapy Enzyme Prodrug Product Mechanism H S V-tk ganciclovir ganciclovir triphosphate blocks DNA synthesis cytosine deaminase 5-fluorocytosine 5-fluorouracil (5-FU) blocks DNA and RNA synthesis (pyrimidine antagoni cytochrome P450 cyclophosphamide phosphoramide mustard DNA alkylating agent; blocks DNA synthesis

26. Strategy of genetically modified tumor vaccines Isolate tumor cells from a patient Alternative – culture other tumor cells- eg, cell line of the same type – i.e. allogeneic cell line Transduce such cells with vector – eg. Retroviral vector harboring cytokine gen e Inject such modified cells into patients Antigens present on allogeneic tumor cells stimulate immune system, which respond to the same antigens present on patient’s tumor Cytokines enhance the response

27. IL-6 and sIL-6R retrovirus melanoma (allogeneic) A. Mackiewicz et al., - Poznań Wadhwa et al., Ann Rev Med. 2002

28. P hysiological angiogenesis in adults is restricte placenta uterus Hair growth Wound healing

29. In healthy organism the action of activators and inhibitors of angiogenesis is balanced Nature Review Cancer

30. Strategies of anti-angiogenic gene therapy

31. Drawbacks of anti-cancer gene therapy Limited access to tumor cells Heterogeneity of tumor cells Emergency of resistant tumor cells Toxicity Advantages of anti-angiogenic gene therapy Little or no toxicity Does not require that therapeutic agent enter any tumor cells nor cross the blood brain barrier Acts independently of tumor cell heterogeneity and tumor type Does not induce acquired drug resistance

32. Recent update KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer-protein required for establishing a bipolar spindle in cell division(kayo et al.,Oct 2017) To date, almost 2600 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide.(The Journal of Gene Medicine) Chimeric antigen receptors (CAR Tcells ) represent another autologous cell‐based therapy targeting tumour ‐associated cell‐surface antigens that had entered the clinic. Latest news on gene therapy – found successful trails in treament of beta- thalassemia

33.  In vivo  approved gene therapy  drugs such as Neovasculgen , Glybera , Defitelio , Rexin -G, Onpattro , Eteplirsen , Spinraza ,, Vitravene as well as Zolgensma directly injected into their target tissue or organ.

34. . Gene Therapy Market 2015-2025, Roots Analysis Report (2017).

35. CONCLUSION In future, this technique will be an everyday used word and change the field of medicine and the potential of treatment is limitless Studies states that increasing percentage of Oral cancer which be higher rates by 2020 and 2030 The development of gene therapy will be definite cure though have an increasing rate of incidence

36. REFERENCES Dubey R.C, A textbook of biotechnology, 1 st edition(2004), S Chand and company, New Delhi Gupta P.K, Elements of Biotechnology, 1 st edition(2001), Rastogi Publications, Meerut. Satyanarayana U, Biotechnology, 1 st edition, Book and allied (P) Ltd, Kolkata. http://www.medindia.net/articles/genetherapy_treat ment.htm http://en.wikipedia.org/wiki/Gene_therapy