genetherapy-deepwater基因療法-深水

1、GENE THERAPY,By Sam Lai and Meng Lee,Gene Therapy,Introduction : What is it?Gene Therapy : A Closer LookHow much did you learn?!Case Study : SCIDModel for Gene Therapy Medical FrameworkDiscussion / Q&A,What is i

2、t?,Gene therapy, which was first conceived in the mid-1970s, aims to insert working copies of genes into cells containing dysfunctional ones treat, cure, or ultimately prevent disease by changing the expression of a per

3、son's genes current gene therapy is primarily experimental, with most human clinical trials only in the research stages Most often in context of treating lethal and disabling diseases, potential also for disease pr

4、evention,Human Genome Project,A 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 person’s genes collecti

5、vely helps 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.,HGP GOALS,Identify aproximately 30,000 genes Determine 3 billion ch

6、emical base pairs that make up human DNAStore information in databasesImprove tools for data analysisAddress ethical, legal and social issues that might arise from this,HGP cont…,Achieve these goals, researchers look

7、at genetic makeup of other organismsThis project is important because the government's dedication to the transfer of technology to the private sector,,Which Cells Targeted?,somatic gene therapy the recipient's g

8、enome 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 inv

9、estigated, at least not humans, although a lot of discussion is being conducted about its value and desirability.,Somatic Stem Cells,Somatic stem cells are remarkable cells in the bodyThese different stem cell types are

10、 targets for gene therapyGenetically treated stem cells, when reintroduced into the patient's body are expected to naturally travel through the blood stream to the bone marrow.,Germline Gene Therapy,Gene therapy in

11、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 the embryo before the stage of differentiation, would

12、 affect all future offspring of that person. This makes an vital distinction, affecting major ethcial issues,Delivery of Genes,Need an efficient method to deliver the gene to live cells.Done via vectors (gene carriers),

13、 delivering therapeutic genes to cells - common vector is virusesAlternative delivery methods seen with use of lipids and proteins,Use of Viruses,Viruses evolved a way of delivering their genes to human cells in path

14、ogenic matter.Take advantage of this, manipulate genome to remove disease genes and insert therapeutic genes,,Risks with GT trials,Viruses can usually infect more than one type of cell. When DNA is injected directly in

15、to a tumor, there is a slight chance that this DNA could unintentionally be introduced into reproductive cells.Other concerns include the possibility that transferred genes could be "overexpressed",,Add a new

16、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,Understanding?,Scientists

17、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,Sickle Cell Anemia,Caused by error in gene that inf

18、orms our body on how to make hemoglobinPrevalent in African AmericansHowever deadly the error is, this increased the survival rate for those who also had malaria in the region,Hurdles…,Most genetic disorders involve mo

19、re than one gene, only few genetic diseases involve merely oneThis multigene disorders also involve the environment, such as diet, exercise, smoking, etc.,,Everything has a price,High costs associated with developing th

20、is technology, and regulations that needed to be implied on it with experimentations are great hurdles for experimenters in this field.,First Human Gene Therapy attempt,Began in 1990, using ex vivo strategy, where patien

21、t 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 se

22、rum cholesterol,First Human GT cont…,Practical approaches, 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

23、fibrosis,GT on Cancer Treatment,Researchers are working to improve the body's natural ability to fight the disease or to make the cancer cells more sensitive to other kinds of treatment, such as chemotherapy Substit

24、ution of a "working" copy of a gene for an inactive or defective gene.,GT on Cancer cont…,Injection of cancer cells with a gene that makes them more sensitive to treatment with an anticancer drug. Introduction

25、 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.,Hurdles Summary,There are many obstacles that preve

26、nt researchers and scientist from developing successful gene therapy techniques.The issues being confronted are the same ones that are faced whenever a powerful new technology is developed.,When All is Said…,A proposed

27、gene therapy trial, or protocol, must be approved by at least two review boards at the scientists' institution. Any studies involving humans must be reviewed with great care.,CASE STUDY: SCID,SCID = Severe Combined

28、Immunodeficiency,What is SCID?,SCID patients can neitherConstruct cell-mediated immune responseMake AntibodiesPatients do not die of SCID itselfMore Boys than Girls,SCID Cases, Past & Present,Not discovered until

29、 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,Science Behind SCID (1),What Happens in SCIDLymphocyte T & B

30、cells do not get developedNormal catabolism of purines deficientBody lack messenger to identify foreign bodiesCannot initiate immune response,Science Behind SCID (2),What Caused SCID?ADA (Adenosine Deaminase) enzyme

31、deficiencyAutosomal recessive inheritance of genes coding for ADA (25%)Cannot Make T cellsSpontaneous Mutation of IL-7 Gene,Science Behind SCID (3),,Science Behind SCID (4),,Possible Therapies,Gem free tent (life long

32、)Regular injections of PEG-ADA Bone Marrow TransplantGene Therapy,GT Curing SCID (1),How mutated genes were discovered?Late 1970s – understood mechanism for immune systemMatch SCID to missing enzymeBrute force / lu

33、ck1983 – ADA cDNA identified & cloned,GT Curing SCID (2),How mutations are correctedRecombinant DNA technologies!!!Gene SplicingInsertion of correct gene into retrovirus vectorSeparate & MultiplyInsert into

34、 patient,GT Curing SCID (3),How to decide on delivery mechanism?Goals:Must take up long-term residence in patientMust be expressed adequatelyMethods:1990 – use patient’s own T cells (ADA)1993 – use blood stem cells

35、 (ADA)1999 – use blood stem cells (X-linked IL-7),GT Curing SCID (4),Gene Therapy SuccessesSo far approximately 80% success rateRestoration of normal cellular immunity in patientsBlood Stem Cells Method done on an in

36、creasing scale,SCID Cure Analysis,Why GT works in SCID?Defect at a single gene locusGenes identified & clonedUndergo irradiation or immunosuppressive chemotherapyTreatment of young children,Discussion of Ethical,

37、 Legal & Social Issues,Many issues & concerns, little answersReal life solutions come from idea brainstormsToday: Sample Medical System Framework,Current Development,Signs of DevelopmentState Law

38、s & Federal Bills which prohibits discrimination based on genetic informationSpecial committee reviewing gene therapy (NIH + FDA)3-5% of all funds for genetics studies must be used for investigation of such issues,

39、Targeted Issues,Regulation of Gene TherapyAssurance of Quality of TreatmentTargeted TreatmentDisease Treatment vs. EnhancementOnly Disease TreatmentFair & Readily Available TreatmentSame Treatment for everyone

40、At an affordable priceProtection of Genetic Information,Assumptions,Possible to isolate and provide treatment only for disease alleles without committing enhancementDevelopment in medical technologies will make medicat

41、ion cheaper in the long runModel applies for a closed country only,Model Philosophy,Possession of genetic information causes many problemsMust have a tightly regulated system in place (multi-level, multi-group)Proposa

42、lCentral Gene Therapy Monitoring Administration,Structure of Medical System,3 Levels, 5 GroupsGovernment:CGTMAReview CommitteePractitioners:DoctorsGene TherapeuticsPatients:Patients,,,,,,,,,,,Patient Treatme

43、nt Process (1),7 StepsDisease Identification1.1 Doctor Identifies Genetic ProblemApplication for Treatment2.1 Doctor Submit ApplicationTreatment Approval3.1 CGTMA Reviews Application,Patient Treatment Process (2)

44、,Preparation of Delivery Material4.1 Gene Therapeutics cure the disease genes, deliver to patient’s stem cellConfirmation of Appropriate Changes5.1 CGTMA confirms for appropriate changesGene Therapy6.1 Doctor con

45、ducts Gene Therapy to Patient,Patient Treatment Process (3),Checkup7.1 Confirm patients received only approved treatment (by CGTMA),Groups Responsibility (1),CGTMACheck validity of genetic treatment (i.e. only targeti

46、ng disease genes)Check for appropriate preparation of genetic material for gene therapyMonitor Treatment by DoctorReview CommitteeDetermine disease genes vs. enhancement genes,Groups Responsibility (2),DoctorsIdenti

47、fying DiseaseSubmitting Application for Gene TherapyConducting Gene TherapyGene TherapeuticsManipulate genes based on applicationBoth group faces penalty for illegal practices,Important Factors,Must have good inter

48、nal and external monitoring by each groupMust be aware and implement policy for patient’s privacy rightsEducation of the general public,Discussion + Q&A,How model answers targeted issuesFlaws with the modelsDiscu