醫(yī)學(xué)遺傳學(xué)教學(xué)課件：Chapter 13 遺傳病的治療

1Chapter13

TheTreatmentofGeneticDisease遺傳病的治療2遺傳性罕見(jiàn)病的治療現(xiàn)狀這么慘嗎？/n/2013/0225/c14739-20586389.html1%？1680萬(wàn)？10%3《探究36種遺傳代謝性疾病在中國(guó)進(jìn)行新生兒篩查的必要性與可行性的前期理論研究》根據(jù)查閱36種疾病的相關(guān)文獻(xiàn)，按其預(yù)后我們將他們分為了以下四類(lèi)。篩后能治愈（16）：楓糖尿病，同型胱氨酸尿癥，酪氨酸血癥Ⅱ型，酪氨酸血癥III型，鳥(niǎo)氨酸氨甲?；D(zhuǎn)移酶缺乏癥，酪氨酸血癥I型，甲基丙二酸血癥，2-甲基丁酰輔酶A脫氫酶缺乏癥，3-甲基巴豆輔酶A羧化酶缺乏癥，多種輔酶A羥化酶缺乏癥，線粒體乙酰乙酰輔酶A硫解酶缺乏癥，肉堿吸收障礙，肉堿棕櫚酰轉(zhuǎn)移酶缺乏Ⅰ型，肉堿棕櫚酰轉(zhuǎn)移酶Ⅱ缺陷，短鏈酰基輔酶A脫氫酶缺陷，中鏈?；o酶A脫氫酶缺陷篩后也完全不能治（1）：戊二酸血癥II型篩后治療還會(huì)有后遺癥（15）：精氨基琥珀酸尿癥，瓜氨酸血癥I型，瓜氨酸血癥II型，精氨酰琥珀酸尿癥，精氨酸血癥，氨甲酰磷酸合成酶缺乏癥，丙酸血癥，異戊酸血癥，戊二酸血癥I型，肉堿/?；鈮A轉(zhuǎn)運(yùn)酶缺陷，長(zhǎng)鏈L-3-羥?；o酶A脫氫酶缺陷，線粒體三功能蛋白缺乏癥，乙基丙二酸腦病，長(zhǎng)鏈?；o酶A脫氫酶缺陷，極長(zhǎng)鏈?；o酶A脫氫酶缺陷當(dāng)前報(bào)道不足無(wú)法清楚該病具體情況（3）：3-甲基戊烯二酰輔酶A水解酶缺乏癥，異丁?；o酶A脫氫酶缺乏癥，2,4-二烯酰輔酶A還原酶缺乏癥4WewilldiscussCurrentStateofTreatmentofGeneticDiseaseSpecialConsiderationsinTreatingGeneticDiseaseTreatmentStrategiesModulationofGeneExpressionModificationofsomaticGenomebytransplantationGeneTherapy5CurrentStateofTreatmentofGeneticDiseaseNowitistheturnofso-calledgeneticdiseasestoenterthisarenaofhopeHomosapiensistheonlyspeciesonearthwhich

intentionallymodifiesexperience,therebymodifying

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

rarediseases,eachofwhichcausesmalignantgrowthinbreasttissueandrequires

individualtreatment”.10Factorsthataffectthetreatmentof

geneticdisease

影響遺傳病治療的因素Genenotidentifiedorpathogenesisnotunderstood

基因未知，或病理未知Prediagnosticfetaldamage

診斷前的胎兒損傷Severephenotypesarethefirsttoberecognized

首發(fā)癥狀為嚴(yán)重表型遺傳診斷產(chǎn)前診斷癥狀前篩查11WewilldiscussCurrentStateofTreatmentofGeneticDiseaseSpecialConsiderationsinTreatingGeneticDiseaseTreatmentStrategiesModulationofGeneExpressionModificationofsomaticGenomebytransplantationGeneTherapy12Theneedforlong-termAssessment

oftreatment

評(píng)價(jià)治療效果需要長(zhǎng)期的觀察Observationtimeisnotlongenoughsubtleinadequacies.長(zhǎng)期觀察才可能發(fā)現(xiàn)一些容易忽視的治療不足Successfultreatmentgivestheopportunitytofindinadequacies.成功的治療使得發(fā)現(xiàn)治療不足成為可能

PKU；

Galactosemia13GeneticHeterogeneityandtreatment

遺傳異質(zhì)性與治療Allelicheterogeneity等位基因異質(zhì)性

LSDs：ERTorASSCLocusheterogeneity基因座異質(zhì)性

PKU:PAHorBH414WewilldiscussCurrentStateofTreatmentofGeneticDiseaseSpecialConsiderationsinTreatingGeneticDiseaseTreatmentStrategiesModulationofGeneExpressionModificationofsomaticGenomebytransplantationGeneTherapy1516TreatmentStrategiesTreatmentofmetabolicAbnormalities

代謝異常的治療DietaryRestriction飲食限制:PKUReplacement補(bǔ)充:congenitalhypothyroidismDiversion分流:familialhypercholesterolemiaInhibition抑制:familialhypercholesterolemiaDepletion耗竭:familialhypercholesterolemia17DiversionDepletionLDLapheresis分離術(shù)cholestyramine消膽氨InhibitionStatins他汀18LDLapheresis

19底物剝奪治療條件：有殘余酶活性產(chǎn)物的適度缺少不會(huì)對(duì)病人造成過(guò)大的危害GBA合成酶20N-butyldeoxynojirmycin(OGT-918)可鞘糖脂的合成OGT918是神經(jīng)酰胺特異的葡萄糖轉(zhuǎn)移酶抑制劑神經(jīng)酰胺特異的葡萄糖轉(zhuǎn)移酶起始鞘糖脂的生物合成，并催化葡糖腦苷脂的合成。2122針對(duì)不同的基因突變類(lèi)型

可采取不同的策略無(wú)義突變錯(cuò)義突變片段突變（缺失或重復(fù)）23活性部位特異的分子伴侶治療Active-Site-SpecificChaperonetherapy1-deoxy-galactonojirimycin(DGJ)forFabryN-nonyl-deoxynojirimycin(NN-DNJ)forGaucher24錯(cuò)義突變25CysticFibrosis26VX-770G551D27PTC124與無(wú)義突變治療28氨基糖苷類(lèi)抗生素（Aminoglycosides）

鏈霉素1940卡那霉素1957妥布霉素丁胺卡那霉素慶大霉素

1963新霉素1970耳毒性,腎毒性,神經(jīng)肌肉阻斷,變態(tài)反應(yīng)29303132PTC1243334Antisense-inducedexonskipping

外顯子跳躍

與缺失重復(fù)突變35漸凍人：ALS重癥肌無(wú)力：MGDuchenneMuscularDystrophy(DMD)363738394041424344454647484950515253TreatmentStrategiesModulationofGeneExpressionSickleCellDisease,Thalassemia

Hydroxyurea羥基脲：ribonucleotidereductaseinhibitor

核酸還原酶抑制劑545556TreatmentStrategiesModificationoftheSomaticGenomebyTransplantation

Bonemarrowtransplantation:

β-thalassemia,MPSI(Hurlersymdrome)

Kidneytransplantation:Fabrydisease

Liver

transplantation:α1AT-deficiency575859骨髓移植－－原理用供體的造血干細(xì)胞和淋巴細(xì)胞完全替代受體的6-12周后，受體組織內(nèi)的巨噬細(xì)胞，包括中樞神經(jīng)系統(tǒng)的小膠質(zhì)細(xì)胞，也被完全替換供體的小膠質(zhì)細(xì)胞分泌病人缺乏的酶神經(jīng)原攝取該酶，并通過(guò)M-6-P受體介導(dǎo)的定位使其到達(dá)溶酶體60小膠質(zhì)細(xì)胞（microglia）

主要分布在大腦、小腦和脊髓的灰質(zhì)內(nèi)，胞體很小，短棒狀，有數(shù)條樹(shù)枝狀突起。突起表面粗糙有棘刺，核呈不規(guī)則的三角形或腎形，染色質(zhì)多，著色深。小膠質(zhì)細(xì)胞有吞噬功能，能作變形運(yùn)動(dòng)，吞噬并清除壞死組織。近年來(lái)，有人認(rèn)為小膠質(zhì)細(xì)胞是由血液中的單核細(xì)胞近移而來(lái)，或來(lái)自血管周?chē)哪┓只?xì)胞。61TreatmentStrategiesGeneTherapy基因治療istheintroductionofageneintoacellforthepurposeofachievingatherapeuticeffect.Greatlong-termpromiseforthetreatmentofhumandisease6263GOF:gainoffunctionLOF:lossoffunction6465PurposeofgenetransferCompensateforaloss-of-functionmutantgene補(bǔ)償功能喪失的突變基因.LysosomalstoragediseasesReplaceor

inactivateadominantmutantgenewhoseabnormalproductcausesthedisease.替換或失活顯性突變基因Pharmacologicaleffect藥理效應(yīng)tocounteracttheeffectsofamutantcellulargeneorgenesortocounteractdiseasepathogenesisinsomeotherway.666768TreatmentStrategiesMultilevelintervention多級(jí)干預(yù)

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