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GENE THERAPY IINTRO.pptx
- 1. GENE THERAPY FUNDAMENTALS OF GENETICS
- 2. PRESENTED TO: DR. SUMAIRA KANWAL PRESENTED BY: TANIA SAEED (FA19-BSI-010)
- 3. CONTENTS What is gene? Gene therapy History of gene therapy Outcomes Functional classification Vectors of gene therapy How to introduce genes? Types of gene therapy Accomplishments Targets Ethical issues
- 4. GENE-THE BASIC CONCEPT Gene is a basic unit of heredity. Genes are segments of DNA. Each gene contains information about a certain trait. Genes are transcribed and translated by the cell to make proteins. Proteins create a visible phenotype. For example, one gene might code for eye color. The gene is used by the cells to make proteins which creates specific pigment color in our eyes.
- 6. GENE THERAPY: An approach of treating diseases by either modifying the expressions of an individual’s genes or correction of abnormal genes. It is intracellular delivery of genes to generate a therapeutic effect by correcting an existing abnormality.
- 8. HISTORY: 1960’s : The concepts of Gene Therapy was introduced. 1972 : Friedman and Roblin authored a paper in Science titled "Gene therapy for human genetic disease.” 1984: A retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes. 1990: The first approved gene therapy in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson. In 1990, a 4-year-old girl named Ashi DiSilva was the first patient to receive gene therapy for SCID (severe combined immunodeficiency). She became a healthy adult with an immune system that was able to fight off most infections.
- 9. OUTCOMES: Gene therapy: replaces a mutated gene with a healthy one. deactivates a gene that isn’t functioning properly. introduces a new gene in the body to help fight the disease. Enhances the effect of a normally functioning gene. Activates the gene that was shut down during fetal life.
- 10. FUNCTIONAL CLASSIFICATION: Base on the purpose of gene therapy it can be: Gene replacement therapy Gene deactivation therapy Transgenesis Gene Enhancement therapy Gene activation therapy
- 11. VECTORS FOR GENE THERAPY: Different carrier systems are used for gene delivery: Viral systems. Non viral systems. Vectors are needed since the genetic material must be transferred across the cell membrane and preferably into the cell nucleus.
- 12. VIRAL VECTORS: Retroviruses Adeno viruses Adeno associated viruses Herpes simplex viruses Retroviruses as vectors of gene is discussed next.
- 13. RETROVIRUSES AS VIRAL VECTORS: The retroviruses are modified to carry genes. The gag, pol, env genes are deleted rendering them incapable of replication inside the host cell. Viruses are then introduced into a culture containing the helper viruses. The helper virus is an engineered virus which is deficient in Ψ segment but contains all other genes for replication. That means it has the genes to produce viral particles but lacks the genes required for packing.
- 14. CONTINUED… The replication deficient but infective retro virus vector carrying the human gene now comes out of the cultured cells. These are introduced into the patient. The virus enters the cell via specific receptors. In the cytoplasm of the human cells, the reverse transcriptase carried by the vector coverts the RNA into DNA, Which is then integrated into the host DNA. The normal human gene can now be expressed. The integrated DNA becomes a permanent part of the chromosome.
- 16. NON-VIRAL VECTORS: Spontaneous uptake by endocytosis Plasmid liposome complex Uncovered plasmids Gene gun methods Electroporation Microinjections Plasmid liposome complex method is discussed next.
- 18. HOW TO INTRODUCE GENES? There are three ways- Ex vivo strategy- Where the patient’s cells are cultured in the laboratory, the new genes are infused into the cells and modified genes are administered back to the patient. In vivo strategy- where the vector is administered directly to the cell. In situ strategy- where the carrier of the gene is injected to the patient either intravenously or directly to the tissues.
- 19. EX-VIVO GENE THERAPY: In this method, the cells are modified outside the body and then transplanted back in again, called the ex vivo because the cells are treated outside the body. Example: 1st gene therapy – to correct deficiency of enzyme, Adenosine deaminase (ADA). Performed on a 4yr old girl Ashanthi DeSilva. Was suffering from SCID- Severe Combined Immunodeficiency. Caused due to defect in gene coding for ADA. Deoxyadenosine accumulate and destroys T lymphocytes. Disrupts immunity , suffer from infectious diseases and die at young age.
- 20. IN VIVO GENE THERAPY: In vivo gene transfer is necessary when cultured cells cannot be re-implanted in patients effectively. Example: In patients with cystic fibrosis, a protein called cystic fibrosis trans- membrane regulator (CFTR) is absent due to a gene defect. In the absence of CFTR chloride ions concentrate within the cells and it draws water from surrounding. This leads to the accumulation of sticky mucous in respiratory tract and lungs. Treated by in vivo replacement of defective gene by adenovirus vector.
- 21. IN SITU GENE THERAPY: In situ gene therapy is a specialized form of in vivo gene therapy where the new genetic material is placed directly into the affected tissue. Examples are injection into a tumor mass with a vector carrying the gene for a toxin, or the injection of a vector carrying a dystrophin gene directly into the muscle of a patient with muscular dystrophy.
- 23. TYPES OF GENE THERAPY: Somatic cells or the Germ line cells are the cells to accept the introduced genes. Based on the type of cells involved the Gene therapy can be: Somatic cell therapy (A somatic cell is any cell of the body except sperm and egg cells.) Germ line therapy (A germ line is the sex cells (eggs and sperm) that are used by sexually reproducing organisms to pass on genes from generation to generation.)
- 24. SOMATIC CELL- GENE THERAPY: single defective cell taken out of an individual’s body. functional version of gene is introduced into cell in a laboratory The cells then reproduce, copies of cells with a corrected version of the gene is injected back into the patient. the good gene ends with the patient and is not inherited by their offspring.
- 26. GERM LINE- GENE THERAPY: normal version of gene is inserted into germ cells. those germ cells will divide normal versions of the gene. any zygote produced as a result of this germ cell will have a correct version of the defective gene and will continue passing it on to their offspring.
- 28. COMPARISON:
- 29. ACCOMPLISHMENTS OF GENE THERAPY: Severe combined Immuno deficiency (SCID)- It is caused by the deficiency of adenosine Deaminase enzyme. The first trial of gene therapy was done on this disease. Follow up studies show the presence of normal immune functions in recipients compatible with life. Restenosis – 13 patients were treated by DNA carrying genes for angiogenesis. All were improved. Breast cancer, prostate cancer, lung cancer, brain cancers and ovarian cancers treated. Activation of Hb F gene in patients of Thalassemia and sickle cell diseases. Trials to enhance the genes of intelligence, height and athleticism. Trials to treat the individuals with genetic predisposition to conditions such as asthma, alcoholism, Alzheimer's disease. Schizophrenia, manic depression and Breast cancer before the onset of clinical manifestations.
- 30. TARGETS: Genetic disorders such as: Duchenne Muscular dystrophy Cystic fibrosis Familial hypercholesterolemia Hemophilia Haemoglobinopathies Gaucher’s disease Albinism Phenyl ketonuria.
- 31. CONTINUED… Acquired diseases such as: Cancers Infectious disease- HIV Neurological disorders Cardiovascular diseases Rheumatoid arthritis Diabetes mellitus
- 32. ETHICAL ISSUES: Who decides what is normal and what is a defect? What kind of an impact will this have on people Germ line gene therapy is much more controversial. It would introduce ‘normal’ human genes into the eggs or sperm of parents, or into the fertilized egg or early embryo of the offspring. The goal would be to change the eventual child's genetic inheritance. This could be done in order to avoid a genetic disease or in order to introduce an ‘enhancing’ genetic variation. There have been no trials of human germ line gene therapy; indeed, there is an informal moratorium in the scientific community on trying such experiments in humans. Both its feasibility and its value are unclear.
- 33. CONTINUED… who are currently living with these disabilities. Will this make them feel worse about themselves? Gene therapy is expensive so will only the rich have access to treatment? What will happen to the poor?