Advance gene therapy

Advance gene therapy

1. Advances In Gene Therapy Presented by Mahendra G S M.pharm Pharmaceutical chemistry

2. A Brief history of gene therapy Advances in biochemistry and molecular biology have helped to understand the genetic basis of inherited diseases . gene therapy was once considered a fantasy (imaginary) It was a dream of researchers to replace the defective genes with good ones and cure the genetic disorder

3. Contd …. However, thousands of individuals already undergone human clinical trials. A great leap in medical science has taken place on the 14 th sept 1990, when a girl suffering from adenosine deaminase deficiency (severe combined immunodeficiency) was treated by transferring the normal gene for adenosine deaminase .

4. What is gene therapy Gene therapy is the process of inserting genes into a person’s cells to treat or prevent disease. The newly introduced gene will encode proteins and correct the deficiencies that occur in genetic disease It is a novel approach to treat, cure, or prevent disease by changing the expression of a person's genes. In the future, this tech may allow doctors to treat disease by inserting genes instead of drugs or surgery

5. Gene therapy stategies 1. Gene augmentation therapy A DNA is inserted to the genome to replace missing gene product. 2. Gene inhibition therapy The antisense gene inhibits the expression of the dominant gene.

6. Approaches for gene therapy 1. Somatic cell gene therapy The non-reproductive cells of an organism are referred to as somatic cells. These are cells of organism other than sperm or egg cells. eg : bone marrow cell,blood cells,skin cell,intesinal cell.

7. At present, all the research on gene therapy is directed to correct the genetic defect in somatic cells. It involves the insertion of a fully functional and expressible gene into a target somatic cell to correct a genetic disease permanently.

8. 2. Germ cell gene therapy the reproductive cells of organism constitute germ cell line. Gene therapy involving the introduction of DNA into germ cell is passed on to the successive generation. Due to ethical and technical reason, germ cell gene therapy is not being attempted at present.

9. Types of gene therapy Ex vivo gene therapy involves the transfer of genes in cultured cells ( e.g : bone marrow cell) which are then introduced into patient. In vivo gene therapy the direct delivery of genes into the cells of a particular tissue is referred to as in vivo gene therapy

10. 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

11. Viruses are used as vectors Viruses are used as vectors to introduce the genetic material inside the bodies. These viruses are inactivated, they are not able to reproduce Adenoviruses Adeno -associated virus Herpes viruses -DNA tumor viruses Retroviruses -RNA tumor viruses

12. 5. Lenti virus 6. Pox viruses 7. Measles viruses Immunogenicity: ability to produce immune response

13. Nonviral Vectors: Liposomes less Immunogenic DNA/lipid complexes are easy to prepare and there is no limit to the size of genes that can be delivered. Because carrier systems lack proteins, they may evoke much less immunogenic responses. More importantly, the cationic lipid systems have much less risk of generating the infectious form or inducing tumorigenic mutations because genes delivered have low integration frequency and cannot replicate or recombine.

14. Nanotechnology in Gene therapy Nanotechnology", is the study of the control of matter on an atomic and molecular scale. Generally nanotechnology deals with structures of the size 100 nanometers or smaller, and involves developing materials or devices within that size The nanotechnology-based approach used by the researchers has minimal toxic side effects to normal cells

15. First Approved Gene Therapy On September 14, 1990 at the U.S. National Institutes of Health, by W. French Anderson M.D. and his colleagues performed the first approved gene therapy procedure on four-year old Ashanthi DeSilva , Born with a rare genetic disease called severe combined immunodeficiency (SCID)

16. 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.

17. 'mending broken hearts' by using gene therapy Novel techniques to “mend broken hearts” using gene therapy and stem cells represent a major new development 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

18. Contd … 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

19. First Real-Time MRI-Guided Gene Therapy for Brain Cancer Neurosurgeons at the University of California and San Diego School of Medicine 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

20. 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.

21. 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)

22. Contd.. 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

23. 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

24. Contd.. 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

25. 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

26. 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

27. 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

28. 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

29. reference biochemistry by u. sathyanarayan , page:no 625-630 https://www.nature.com/subjects/gene-therapy http://stm.sciencemag.org/content/2/38/38ec102 http://biologywriter.com/on-science/articles/genetherapy/ http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2010.04424.x/full

30. Thank you