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1、GENE THERAPYGENE THERAPYAny procedure intended to treat or alleviate disease by genetically modifying the cells of a patientGENE THERAPYq Delivery mechanismEx vivoIn vivoq Type of cells modifiedGerm-line cellsSomatic cellsq Mechanism of modificationGene augmentation/supplementationGene replacementTa
2、rgeted inhibition of gene expressionTargeted killing of specific cellsDELIVERY 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 patient(In vivo)(ex vivo)DELIVERY MECHANIS
3、MSq Germ-line gene therapyModification of gametes, zygote or early embryoPermanent and transmissibleBanned due to ethical issuesq Somatic cell gene therapyModification of somatic cells, tissues etc Confined to the patientTYPES OF CELLS MODIFIED Targeted at disorders where pathogenesis is reversible
4、Recessive disorders are more amendable to treatment than dominant disorders Gain-of-function mutations are untreatable by GATMechanism of modification1. Gene augmentationMechanism of modification2. Gene replacementMechanism of modification 3. Targeted killing of specific cellsMechanism of modificati
5、on4.Targeted inhibition of gene expressionGain-of-function diseases where mutant gene is producing a harmful proteinAmenability to gene therapy qMode of inheritanceqIdentity of molecular defectqNature of mutation productqAccessibility of target cells and amenability to cell cultureqSize of coding DN
6、AqControl of gene expression Gene transferCloned geneIntegrated geneEpisomal geneCell division Vectors in useViralRetro-Adeno-Adeno-associated-Herpes simplex- Non-viralNaked DNA/PlasmidliposomesRetrovirusescreate cDNA copies from the viral RNA genome integrate into the human genomeMaximum insert siz
7、e 7-7.5 kbPreexisting host immunity unlikelyCan only transduce dividing cellsMay cause insertional mutagenesisRetrovirusesLentiviruses (e.g HIV)Maximum insert size 7-7.5 kbCan transduce non-dividing cellsMay cause insertional mutagenesisAdenovirusesAre double stranded DNA genome that cause respirato
8、ry, intestinal, and eye infections in humansMaximum insert size 30 kbCan transduce dividing and non-dividing cellsExtensive unwanted immunological responses Episomal- do not integrateHave to be reinserted when more cells dividePre-existing host immunitysmall, single stranded DNA virusesproductive in
9、fection only with co-infection by another virusinsert genetic material at a specific point on chromosome 19Low information capacity- 4.0 KbAdeno-associated VirusesComplex ds DNAEstablish life long latent infections as non-integrated extra chromosomal elementsinformation capacity 30 KbHerpes simplex
10、VirusesLiposomesPlasmidsGene therapy for ADA deficiencyThree approaches for treatmentBone marrow transplantEnzymatic replacementGene therapyADA small geneClonedT-cells accessible and easy to culture in vitroRecessive inheritanceGene expression is not tightly controlledFirst gene therapy trial for AD
11、A deficiency -1990Gene therapy for OTC deficiencyIn 1999, 18-year-old Jesse Gelsinger died from multiple organ failure 4 days after treatment for ornithine transcarbomylase deficiency.Death was triggered by severe immune response to the adenoviral vector Gene therapy for SCID-X1Mutation in gene for
12、gc-cytokine receptor10 month follow-up two patients T-cells expressed normal gc-cytokine receptorHowever, in a French study 3/10 patients developed leukemia within three yearsIntegration of retroviral DNA next to an oncogeneqAdverse response to the vectorqInsertional mutatgenesis resulting in malignant neoplasiaqInsertional inactivation of an essential geneqViruses may infect surrounding health tissuesqOverexpression of the inserted gene may lead to so much protein that it may become harmfulRisks associated with gene therapy
