GENETHERAPYDeepwater：基因療法深水-2課件

1、GENE THERAPYBy Sam Lai and Meng Lee第1頁，共56頁。Gene TherapyIntroduction : What is it?Gene Therapy : A Closer LookHow much did you learn?!Case Study : SCIDModel for Gene Therapy Medical FrameworkDiscussion / Q&A第2頁，共56頁。What is it?Gene therapy, which was first conceived in the mid-1970s, aims to insert

2、working copies of genes into cells containing dysfunctional ones treat, cure, or ultimately prevent disease by changing the expression of a persons genes current gene therapy is primarily experimental, with most human clinical trials only in the research stages Most often in context of treating leth

3、al and disabling diseases, potential also for disease prevention第3頁，共56頁。第4頁，共56頁。Human Genome ProjectA genome is all the DNA in an organism, including its genes. Genes carry information for making all the proteins required by all organisms Variations in structure of persons genes collectively helps

4、 define us as individualsRationale for GT is based on knowledge of the human genetic code Began formally in 1990, set as a 13 year project. 第5頁，共56頁。HGP GOALS Identify aproximately 30,000 genes Determine 3 billion chemical base pairs that make up human DNAStore information in databasesImprove tools

5、for data analysisAddress ethical, legal and social issues that might arise from this第6頁，共56頁。HGP contAchieve these goals, researchers look at genetic makeup of other organismsThis project is important because the governments dedication to the transfer of technology to the private sector 第7頁，共56頁。第8頁

6、，共56頁。Which Cells Targeted?somatic gene therapy the recipients genome is changed, but the change is not passed along to the next generation germline gene therapy, the sex cells are changed with the goal of passing these changes to their offspring. But, this is not being actively investigated, at lea

7、st not humans, although a lot of discussion is being conducted about its value and desirability. 第9頁，共56頁。Somatic Stem Cells Somatic stem cells are remarkable cells in the bodyThese different stem cell types are targets for gene therapyGenetically treated stem cells, when reintroduced into the patie

8、nts body are expected to naturally travel through the blood stream to the bone marrow. 第10頁，共56頁。Germline Gene TherapyGene therapy in germline cells has the potential to affect not only the individual, but also their children as well. Any genetic changes in the reproductive cells or changes made to

9、the embryo before the stage of differentiation, would affect all future offspring of that person. This makes an vital distinction, affecting major ethcial issues 第11頁，共56頁。Delivery of GenesNeed an efficient method to deliver the gene to live cells.Done via vectors (gene carriers), delivering therape

10、utic genes to cells - common vector is virusesAlternative delivery methods seen with use of lipids and proteins第12頁，共56頁。Use of VirusesViruses evolved a way of delivering their genes to human cells in pathogenic matter.Take advantage of this, manipulate genome to remove disease genes and insert ther

11、apeutic genes第13頁，共56頁。 第14頁，共56頁。Risks with GT trialsViruses can usually infect more than one type of cell. When DNA is injected directly into a tumor, there is a slight chance that this DNA could unintentionally be introduced into reproductive cells.Other concerns include the possibility that tran

12、sferred genes could be overexpressed第15頁，共56頁。 第16頁，共56頁。Add a new chromosome?Experimentation seen with introduction of 47th chromosome Exist along 46th chromosome, large vector capable carrying genetic code, that hopefully the immune system would not attack第17頁，共56頁。第18頁，共56頁。Understanding? Scienti

13、sts know little about function of the thousands of genes. Attempting therapy without this knowledge would address few genes of a particular diseasei.e. Sickle Cell Anemia第19頁，共56頁。Sickle Cell AnemiaCaused by error in gene that informs our body on how to make hemoglobinPrevalent in African AmericansH

14、owever deadly the error is, this increased the survival rate for those who also had malaria in the region第20頁，共56頁。Hurdles Most genetic disorders involve more than one gene, only few genetic diseases involve merely oneThis multigene disorders also involve the environment, such as diet, exercise, smo

15、king, etc.第21頁，共56頁。第22頁，共56頁。Everything has a priceHigh costs associated with developing this technology, and regulations that needed to be implied on it with experimentations are great hurdles for experimenters in this field.第23頁，共56頁。First Human Gene Therapy attemptBegan in 1990, using ex vivo st

16、rategy, where patient cells were cultivated in laboratory and incubated with vectorstransplanted back into the patientAttempted to treat 2 genetic disorders, including children with immune defiency as well as people with high levels of serum cholesterol第24頁，共56頁。First Human GT contPractical approach

17、es, delivering genes based on so-called in vivo GT where viruses are directly given to patientsFirst model was dependent on a version of adenovirus to treat cystic fibrosis第25頁，共56頁。GT on Cancer TreatmentResearchers are working to improve the bodys natural ability to fight the disease or to make the

18、 cancer cells more sensitive to other kinds of treatment, such as chemotherapy Substitution of a working copy of a gene for an inactive or defective gene. 第26頁，共56頁。GT on Cancer contInjection of cancer cells with a gene that makes them more sensitive to treatment with an anticancer drug. Introductio

19、n of the multidrug resistance gene into stem cells. The MDR gene is used to make the stem cells more resistant to the side effects of the high doses of anticancer drugs. 第27頁，共56頁。Hurdles SummaryThere are many obstacles that prevent researchers and scientist from developing successful gene therapy t

20、echniques.The issues being confronted are the same ones that are faced whenever a powerful new technology is developed. 第28頁，共56頁。When All is SaidA proposed gene therapy trial, or protocol, must be approved by at least two review boards at the scientists institution. Any studies involving humans mus

21、t be reviewed with great care. 第29頁，共56頁。CASE STUDY: SCIDSCID = Severe Combined Immunodeficiency第30頁，共56頁。What is SCID?SCID patients can neitherConstruct cell-mediated immune responseMake AntibodiesPatients do not die of SCID itselfMore Boys than Girls第31頁，共56頁。SCID Cases, Past & PresentNot discover

22、ed until early 1960sOccur in 1 out of 1.000,000“Bubble Boy” David VetterSpent 12 years in Texas Hospital Sterile TentUsually not discovered until too late第32頁，共56頁。Science Behind SCID (1)What Happens in SCIDLymphocyte T & B cells do not get developedNormal catabolism of purines deficientBody lack me

23、ssenger to identify foreign bodiesCannot initiate immune response第33頁，共56頁。Science Behind SCID (2)What Caused SCID?ADA (Adenosine Deaminase) enzyme deficiencyAutosomal recessive inheritance of genes coding for ADA (25%)Cannot Make T cellsSpontaneous Mutation of IL-7 Gene第34頁，共56頁。Science Behind SCID

24、 (3) 第35頁，共56頁。Science Behind SCID (4) 第36頁，共56頁。Possible TherapiesGem free tent (life long)Regular injections of PEG-ADA Bone Marrow TransplantGene Therapy第37頁，共56頁。GT Curing SCID (1)How mutated genes were discovered?Late 1970s understood mechanism for immune systemMatch SCID to missing enzymeBrute

25、 force / luck1983 ADA cDNA identified & cloned第38頁，共56頁。GT Curing SCID (2)How mutations are correctedRecombinant DNA technologies!Gene SplicingInsertion of correct gene into retrovirus vectorSeparate & MultiplyInsert into patient第39頁，共56頁。GT Curing SCID (3)How to decide on delivery mechanism?Goals:M

26、ust take up long-term residence in patientMust be expressed adequatelyMethods:1990 use patients own T cells (ADA)1993 use blood stem cells (ADA)1999 use blood stem cells (X-linked IL-7)第40頁，共56頁。GT Curing SCID (4)Gene Therapy SuccessesSo far approximately 80% success rateRestoration of normal cellul

27、ar immunity in patientsBlood Stem Cells Method done on an increasing scale第41頁，共56頁。SCID Cure AnalysisWhy GT works in SCID?Defect at a single gene locusGenes identified & clonedUndergo irradiation or immunosuppressive chemotherapyTreatment of young children第42頁，共56頁。Discussion of Ethical, Legal & So

28、cial IssuesMany issues & concerns, little answersReal life solutions come from idea brainstormsToday: Sample Medical System Framework第43頁，共56頁。Current DevelopmentSigns of DevelopmentState Laws & Federal Bills which prohibits discrimination based on genetic informationSpecial committee reviewing gene

29、 therapy (NIH + FDA)3-5% of all funds for genetics studies must be used for investigation of such issues第44頁，共56頁。Targeted IssuesRegulation of Gene TherapyAssurance of Quality of TreatmentTargeted TreatmentDisease Treatment vs. EnhancementOnly Disease TreatmentFair & Readily Available TreatmentSame

30、Treatment for everyoneAt an affordable priceProtection of Genetic Information第45頁，共56頁。AssumptionsPossible to isolate and provide treatment only for disease alleles without committing enhancementDevelopment in medical technologies will make medication cheaper in the long runModel applies for a close

31、d country only第46頁，共56頁。Model PhilosophyPossession of genetic information causes many problemsMust have a tightly regulated system in place (multi-level, multi-group)ProposalCentral Gene Therapy Monitoring Administration第47頁，共56頁。Structure of Medical System3 Levels, 5 GroupsGovernment:CGTMAReview Co

32、mmitteePractitioners:DoctorsGene TherapeuticsPatients:Patients第48頁，共56頁。Patient Treatment Process (1)7 StepsDisease Identification1.1 Doctor Identifies Genetic ProblemApplication for Treatment2.1 Doctor Submit ApplicationTreatment Approval3.1 CGTMA Reviews Application第49頁，共56頁。Patient Treatment Process (2)Preparation of Delivery Material4.1 Gene Therapeutics cure the disease genes, deliver to patients stem cellConf