GENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级课件

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1、GENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级GENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级GENE THERAPYGENE THERAPYAny procedure intended to treat or alleviate disease by genetically modifying the cells of a patientGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级GENE THERAPYq Delivery mec

2、hanismEx vivoIn vivoq Type of cells modified Germ-line cells Somatic cellsq Mechanism of modification Gene augmentation/supplementation Gene replacement Targeted inhibition of gene expression Targeted killing of specific cellsGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级DELIVERY MECHANISMSDELIV

3、ERY MECHANISMSin vivo genetic material transferred directly into cells within a patientex vivo cells are removed from the patient,genetically modified and transplanted back into the patientGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级(In vivo)(ex vivo)DELIVERY MECHANISMSDELIVERY MECHANISMSGENET

4、HERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级q Modification of gametes,zygote or early embryo Permanent and transmissible Banned due to ethical issuesq Modification of somatic cells,tissues etc Confined to the patientTYPES OF CELLS MODIFIEDGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级 Targeted

5、at disorders where pathogenesis is reversible Recessive disorders are more amendable to treatment than dominant disorders Gain-of-function mutations are untreatable by GATMechanism of modificationMechanism of modification1.Gene augmentation1.Gene augmentationGENETHERAPYShifaCollegeofMedicineClassof基

6、因疗法希法医学院级Mechanism of modificationMechanism of modification2.Gene replacement2.Gene replacementGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级Mechanism of modificationMechanism of modification 3.Targeted killing of specific 3.Targeted killing of specific cellscellsGENETHERAPYShifaCollegeofMedicin

7、eClassof基因疗法希法医学院级Mechanism of modificationMechanism of modification4.4.Targeted inhibition of gene expressionGain-of-function diseases where mutant gene is producing a harmful proteinGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级Amenability to gene therapy Amenability to gene therapy q Mode of

8、inheritanceq Identity of molecular defectq Nature of mutation productq Accessibility of target cells and amenability to cell cultureq Size of coding DNAq Control of gene expression GENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级Gene transferGene transferCloned geneIntegrated geneEpisomal geneCell

9、 divisionGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级 Vectors in use Vectors in use ViralViral Retro-Adeno-Adeno-associated-Herpes simplex-Non-viralNon-viral Naked DNA/Plasmid liposomesGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级RetrovirusesRetrovirusescreate cDNA copies from the viral R

10、NA genome integrate into the human genomeMaximum insert size 7-7.5 kbPreexisting host immunity unlikelyCan only transduce dividing cellsMay cause insertional mutagenesisGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级RetrovirusesRetrovirusesLentiviruses(e.g HIV)Maximum insert size 7-7.5 kbCan tran

11、sduce non-dividing cellsMay cause insertional mutagenesisGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级AdenovirusesAdenovirusesAre double stranded DNA genome that cause respiratory,intestinal,and eye infections in humansMaximum insert size 30 kbCan transduce dividing and non-dividing cellsExtens

12、ive unwanted immunological responses Episomal-do not integrateHave to be reinserted when more cells dividePre-existing host immunityGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级 small,single stranded DNA viruses productive infection only with co-infection by another virus insert genetic materia

13、l at a specific point on chromosome 19 Low information capacity-4.0 KbAdeno-associatedAdeno-associated VirusesVirusesGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级 Complex ds DNA Establish life long latent infections as non-integrated extra chromosomal elements information capacity 30 KbHerpes s

14、implex VirusesHerpes simplex VirusesGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级LiposomesLiposomesGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级PlasmidsPlasmidsGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级Gene therapy for ADA Gene therapy for ADA deficiencydeficiency Three approaches

15、for treatment Bone marrow transplant Enzymatic replacement Gene therapy ADA small gene Cloned T-cells accessible and easy to culture in vitro Recessive inheritance Gene expression is not tightly controlledGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级First gene First gene therapy therapy trial f

16、or trial for ADA ADA deficiency-deficiency-19901990GENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级Gene therapy for OTC Gene therapy for OTC deficiencydeficiencyIn 1999,18-year-old Jesse Gelsinger died from multiple organ failure 4 days after treatment for ornithine transcarbomylase deficiency.Dea

17、th was triggered by severe immune response to the adenoviral vector GENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级Gene therapy for SCID-X1Gene therapy for SCID-X1 Mutation in gene for gc-cytokine receptor 10 month follow-up two patients T-cells expressed normal gc-cytokine receptor However,in a

18、French study 3/10 patients developed leukemia within three years Integration of retroviral DNA next to an oncogeneGENETHERAPYShifaCollegeofMedicineClassof基因疗法希法医学院级q Adverse response to the vectorq Insertional mutatgenesis resulting in malignant neoplasiaq Insertional inactivation of an essential geneq Viruses may infect surrounding health tissuesq Overexpression of the inserted gene may lead to so much protein that it may become harmfulRisks associated with Risks associated with gene therapygene therapy