医学遗传学教学课件：Chapter 13 遗传病的治疗

1Chapter13

TheTreatmentofGeneticDisease遗传病的治疗2遗传性罕见病的治疗现状这么惨吗？/n/2013/0225/c14739-20586389.html1%？1680万？10%3《探究36种遗传代谢性疾病在中国进行新生儿筛查的必要性与可行性的前期理论研究》根据查阅36种疾病的相关文献，按其预后我们将他们分为了以下四类。筛后能治愈（16）：枫糖尿病，同型胱氨酸尿症，酪氨酸血症Ⅱ型，酪氨酸血症III型，鸟氨酸氨甲酰基转移酶缺乏症，酪氨酸血症I型，甲基丙二酸血症，2-甲基丁酰辅酶A脱氢酶缺乏症，3-甲基巴豆辅酶A羧化酶缺乏症，多种辅酶A羟化酶缺乏症，线粒体乙酰乙酰辅酶A硫解酶缺乏症，肉碱吸收障碍，肉碱棕榈酰转移酶缺乏Ⅰ型，肉碱棕榈酰转移酶Ⅱ缺陷，短链酰基辅酶A脱氢酶缺陷，中链酰基辅酶A脱氢酶缺陷筛后也完全不能治（1）：戊二酸血症II型筛后治疗还会有后遗症（15）：精氨基琥珀酸尿症，瓜氨酸血症I型，瓜氨酸血症II型，精氨酰琥珀酸尿症，精氨酸血症，氨甲酰磷酸合成酶缺乏症，丙酸血症，异戊酸血症，戊二酸血症I型，肉碱/酰基肉碱转运酶缺陷，长链L-3-羟酰基辅酶A脱氢酶缺陷，线粒体三功能蛋白缺乏症，乙基丙二酸脑病，长链酰基辅酶A脱氢酶缺陷，极长链酰基辅酶A脱氢酶缺陷当前报道不足无法清楚该病具体情况（3）：3-甲基戊烯二酰辅酶A水解酶缺乏症，异丁酰基辅酶A脱氢酶缺乏症，2,4-二烯酰辅酶A还原酶缺乏症4WewilldiscussCurrentStateofTreatmentofGeneticDiseaseSpecialConsiderationsinTreatingGeneticDiseaseTreatmentStrategiesModulationofGeneExpressionModificationofsomaticGenomebytransplantationGeneTherapy5CurrentStateofTreatmentofGeneticDiseaseNowitistheturnofso-calledgeneticdiseasestoenterthisarenaofhopeHomosapiensistheonlyspeciesonearthwhich

intentionallymodifiesexperience,therebymodifying

naturalselection.6CurrentStateofTreatmentofGeneticDiseaseSingle-GeneDiseases7215230322009年2014年2个/天8325200820133509“Soontherewillbenodiseasecalledbreastcancer,”saysDraghia-Akli.Instead,thecatch-alltermwillbereplacedby“alargenumberof

rarediseases,eachofwhichcausesmalignantgrowthinbreasttissueandrequires

individualtreatment”.10Factorsthataffectthetreatmentof

geneticdisease

影响遗传病治疗的因素Genenotidentifiedorpathogenesisnotunderstood

基因未知，或病理未知Prediagnosticfetaldamage

诊断前的胎儿损伤Severephenotypesarethefirsttoberecognized

首发症状为严重表型遗传诊断产前诊断症状前筛查11WewilldiscussCurrentStateofTreatmentofGeneticDiseaseSpecialConsiderationsinTreatingGeneticDiseaseTreatmentStrategiesModulationofGeneExpressionModificationofsomaticGenomebytransplantationGeneTherapy12Theneedforlong-termAssessment

oftreatment

评价治疗效果需要长期的观察Observationtimeisnotlongenoughsubtleinadequacies.长期观察才可能发现一些容易忽视的治疗不足Successfultreatmentgivestheopportunitytofindinadequacies.成功的治疗使得发现治疗不足成为可能

PKU；

Galactosemia13GeneticHeterogeneityandtreatment

遗传异质性与治疗Allelicheterogeneity等位基因异质性

LSDs：ERTorASSCLocusheterogeneity基因座异质性

PKU:PAHorBH414WewilldiscussCurrentStateofTreatmentofGeneticDiseaseSpecialConsiderationsinTreatingGeneticDiseaseTreatmentStrategiesModulationofGeneExpressionModificationofsomaticGenomebytransplantationGeneTherapy1516TreatmentStrategiesTreatmentofmetabolicAbnormalities

代谢异常的治疗DietaryRestriction饮食限制:PKUReplacement补充:congenitalhypothyroidismDiversion分流:familialhypercholesterolemiaInhibition抑制:familialhypercholesterolemiaDepletion耗竭:familialhypercholesterolemia17DiversionDepletionLDLapheresis分离术cholestyramine消胆氨InhibitionStatins他汀18LDLapheresis

19底物剥夺治疗条件：有残余酶活性产物的适度缺少不会对病人造成过大的危害GBA合成酶20N-butyldeoxynojirmycin(OGT-918)可鞘糖脂的合成OGT918是神经酰胺特异的葡萄糖转移酶抑制剂神经酰胺特异的葡萄糖转移酶起始鞘糖脂的生物合成，并催化葡糖脑苷脂的合成。2122针对不同的基因突变类型

可采取不同的策略无义突变错义突变片段突变（缺失或重复）23活性部位特异的分子伴侣治疗Active-Site-SpecificChaperonetherapy1-deoxy-galactonojirimycin(DGJ)forFabryN-nonyl-deoxynojirimycin(NN-DNJ)forGaucher24错义突变25CysticFibrosis26VX-770G551D27PTC124与无义突变治疗28氨基糖苷类抗生素（Aminoglycosides）

链霉素1940卡那霉素1957妥布霉素丁胺卡那霉素庆大霉素

1963新霉素1970耳毒性,肾毒性,神经肌肉阻断,变态反应29303132PTC1243334Antisense-inducedexonskipping

外显子跳跃

与缺失重复突变35渐冻人：ALS重症肌无力：MGDuchenneMuscularDystrophy(DMD)363738394041424344454647484950515253TreatmentStrategiesModulationofGeneExpressionSickleCellDisease,Thalassemia

Hydroxyurea羟基脲：ribonucleotidereductaseinhibitor

核酸还原酶抑制剂545556TreatmentStrategiesModificationoftheSomaticGenomebyTransplantation

Bonemarrowtransplantation:

β-thalassemia,MPSI(Hurlersymdrome)

Kidneytransplantation:Fabrydisease

Liver

transplantation:α1AT-deficiency575859骨髓移植－－原理用供体的造血干细胞和淋巴细胞完全替代受体的6-12周后，受体组织内的巨噬细胞，包括中枢神经系统的小胶质细胞，也被完全替换供体的小胶质细胞分泌病人缺乏的酶神经原摄取该酶，并通过M-6-P受体介导的定位使其到达溶酶体60小胶质细胞（microglia）

主要分布在大脑、小脑和脊髓的灰质内，胞体很小，短棒状，有数条树枝状突起。突起表面粗糙有棘刺，核呈不规则的三角形或肾形，染色质多，着色深。小胶质细胞有吞噬功能，能作变形运动，吞噬并清除坏死组织。近年来，有人认为小胶质细胞是由血液中的单核细胞近移而来，或来自血管周围的末分化细胞。61TreatmentStrategiesGeneTherapy基因治疗istheintroductionofageneintoacellforthepurposeofachievingatherapeuticeffect.Greatlong-termpromiseforthetreatmentofhumandisease6263GOF:gainoffunctionLOF:lossoffunction6465PurposeofgenetransferCompensateforaloss-of-functionmutantgene补偿功能丧失的突变基因.LysosomalstoragediseasesReplaceor

inactivateadominantmutantgenewhoseabnormalproductcausesthedisease.替换或失活显性突变基因Pharmacologicaleffect药理效应tocounteracttheeffectsofamutantcellulargeneorgenesortocounteractdiseasepathogenesisinsomeotherway.666768TreatmentStrategiesMultilevelintervention多级干预

supportivetreatment….….….education6970TheCurrentStateofTreatmentofGeneticDiseaseMultifactorialDiseasesSingle-GeneDiseasesSpecialConsiderationsinTreatingGeneticDiseaseTheNeedforLong-termAssessmentofTreatmentGeneticHeterogeneityandTreatmentTreatmentStrategiesTreatmentofMetabolicAbnormalities