Gene therapy for glycogen storage disease type III
III 型糖原累积病的基因治疗
基本信息
- 批准号:10444983
- 负责人:
- 金额:$ 70.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAgeAge-MonthsBacillus subtilisBiochemicalBiological MarkersBloodCanis familiarisCapsidCardiacCarrying CapacitiesCellsChickensClinical TrialsComplementary DNACytomegalovirusCytotoxic T-LymphocytesDNA cassetteDataDefectDependovirusDevelopmentDextrinsDiseaseDoseEnhancersEnzymesFemaleFoundationsGenderGenesGlycogenGlycogen Debranching EnzymeGlycogen Storage Disease Type IIIGoalsHepatocyteHepatotoxicityHereditary DiseaseHistologicHumanImmune responseInfantInheritedKnock-outLaboratoriesLeadLiverLiver CirrhosisLiver FailureLiver diseasesMeasurementMediatingMetabolic DiseasesMorbidity - disease rateMusMuscleMuscle CellsMuscle FibersMuscle functionMutationMyocardiumMyopathyOncogenesOpen Reading FramesOrganOutcomePatientsRecording of previous eventsResearchSafetySerotypingSerumSkeletal MuscleTechnologyTestingTissuesToxic effectTranslatingTranslationsUrineadaptive immune responseadeno-associated viral vectoragedanalogbeta Actincanine modelcell typeclinical candidateclinical translationclinically translatablecurative treatmentsde-immunizationdietaryeffective therapyefficacy evaluationexperiencegene therapygenome editinghuman diseasehumanized mouseinnovationliver functionmortalitymouse modelnovelpreventpromoterresponsesexskeletaltherapeutic candidatetherapeutic developmenttherapy developmenttherapy outcometransduction efficiencytransgene expressionurinaryvector
项目摘要
ABSTRACT
Glycogen storage disease type III (GSD III) is an autosomal recessive inherited disorder caused by deficiency
of glycogen debranching enzyme (GDE) that leads to excessive accumulation of abnormal glycogen (limit
dextrin) in muscle and liver tissues. The majority of patients (~85%) have both muscle and liver involvement
(GSD IIIa) while others have disease limited to the liver (GSD IIIb). In absence of an effective therapy, patients
with GSD III are experiencing progressive liver failure and muscle damage accompanied by increased morbidity
and mortality. Adeno-associated virus (AAV) mediated gene therapy has shown promise for treating inherited
muscle and liver disorders with successful translation to clinical trials. However, this approach has not been
advanced for GSD III because AAV is not capable of delivering the large (4.6 kb) human GDE cDNA, due to its
small packaging capacity. We have developed an innovative gene therapy approach with AAV9 in a mouse
model of GSD IIIa with two key components incorporated 1) a small bacterial GDE analog to overcome the
limitation of small AAV carrying capacity; and 2) a novel immunotolerizing dual promoter to prevent cytotoxic T
lymphocyte (CTL) response to the bacterial enzyme and enable long-term Pullulanase expression in all affected
tissues. The overall objective of this project is to identify a path forward for clinical translation of this promising
therapy. It is commonly known that the therapeutic outcomes of AAV vectors in mouse models does not always
translate into human. Current AAV serotypes, especially AAV9, transduce muscle and liver in mice with high
efficiency; however, high doses of AAV9 required to transduce skeletal muscles in human patients can led to
adverse hepatotoxicity or even liver failure. In this proposal, we aim to identify a lead therapeutic candidate AAV
vector in GSD IIIa mice using high potency cross-species compatible AAV capsids (ccAAVs) containing a de-
immunized transgene expression cassette to minimize gene therapy related immune responses and reduce the
effective vector dose (Aim 1a). We will validate the lead AAV vector in GSD IIIa patient muscle cells and human
liver chimeric mice to increase its clinical translatability (Aim 1b). We will then examine the long-term efficacy of
the lead AAV vector in GSD IIIa mice (Aim 2), and test its safety and efficacy in GSD IIIa dogs (Aim 3). Data
generated from the proposed studies will lay the foundation for translating this innovative gene therapy to patients
with GSD III. The concept of using a bacterial enzyme to treat human diseases through gene therapy may open
up new alternatives for therapeutic development for metabolic disorders caused by defects in large genes. The
immunotolerizing dual promoter technology can also be broadly used for treating other conditions that affect
multiple tissues with gene therapy.
抽象的
糖原累积病 III 型(GSD III)是一种由糖原缺乏引起的常染色体隐性遗传性疾病
糖原脱支酶(GDE)导致异常糖原过度积累(限制
糊精)存在于肌肉和肝脏组织中。大多数患者(约 85%)有肌肉和肝脏受累
(GSD IIIa),而其他人的疾病仅限于肝脏 (GSD IIIb)。在缺乏有效治疗的情况下,患者
患有 GSD III 的患者正在经历进行性肝衰竭和肌肉损伤,并伴有发病率增加
和死亡率。腺相关病毒(AAV)介导的基因治疗已显示出治疗遗传性疾病的希望
肌肉和肝脏疾病已成功转化为临床试验。然而,这种做法并未得到
对于 GSD III 来说是先进的,因为 AAV 无法传递大的 (4.6 kb) 人类 GDE cDNA,因为它的
包装容量小。我们在小鼠体内开发了一种创新的 AAV9 基因治疗方法
GSD IIIa 模型包含两个关键组件:1) 一个小的细菌 GDE 类似物,以克服
小型 AAV 运载能力的限制; 2) 一种新型免疫耐受双启动子,可预防细胞毒性 T
淋巴细胞(CTL)对细菌酶作出反应,并使所有受影响的细胞能够长期表达支链淀粉酶
组织。该项目的总体目标是确定这一有前途的临床转化的前进道路
治疗。众所周知,AAV 载体在小鼠模型中的治疗效果并不总是
翻译成人类。目前的 AAV 血清型,尤其是 AAV9,可在高抗病毒小鼠体内转导肌肉和肝脏。
效率;然而,在人类患者中转导骨骼肌所需的高剂量 AAV9 可能会导致
不良肝毒性甚至肝功能衰竭。在本提案中,我们的目标是确定一种主要的候选治疗药物 AAV
GSD IIIa 小鼠中使用含有 de-的高效跨物种兼容 AAV 衣壳 (ccAAV)
免疫转基因表达盒,以最大限度地减少基因治疗相关的免疫反应并减少
有效载体剂量(目标 1a)。我们将在 GSD IIIa 患者肌肉细胞和人类中验证先导 AAV 载体
肝脏嵌合小鼠以增加其临床可转化性(目标 1b)。然后我们将检查长期疗效
在 GSD IIIa 小鼠中研究领先的 AAV 载体(目标 2),并在 GSD IIIa 狗中测试其安全性和有效性(目标 3)。数据
拟议研究产生的结果将为将这种创新基因疗法转化为患者奠定基础
与 GSD III。利用细菌酶通过基因疗法治疗人类疾病的概念或将开启
为大基因缺陷引起的代谢紊乱的治疗开发寻找新的替代方案。这
免疫耐受双启动子技术还可广泛用于治疗影响其他疾病的疾病
多个组织进行基因治疗。
项目成果
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Baodong Sun其他文献
Baodong Sun的其他文献
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{{ truncateString('Baodong Sun', 18)}}的其他基金
Gene therapy for glycogen storage disease type III
III 型糖原累积病的基因治疗
- 批准号:
10599208 - 财政年份:2022
- 资助金额:
$ 70.75万 - 项目类别:
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