Gene Therapy Clinical Candidate Development for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症的基因治疗临床候选药物开发
基本信息
- 批准号:10540348
- 负责人:
- 金额:$ 42.92万
- 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:2022-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAmmoniaAnimal ModelAnorexiaBiotechnologyBirthBrainCarbamyl PhosphateCerebral EdemaClinicalClinical ProtocolsCodon NucleotidesComaComplementary DNACryopreservationDNA cassetteDataDefectDependovirusDevelopmentDietDiseaseDisease modelDoseDrug Metabolic DetoxicationEncephalopathiesEnhancersEnzymatic BiochemistryEnzymesGene DeliveryGene Transduction AgentGenesGeneticGenetic DiseasesGenomeGlutamineGoalsHepaticHepatocyteHereditary DiseaseHumanHybridsHyperammonemiaHyperargininemiaHypoventilationImpairmentIncidenceInfantKnockout MiceLaboratoriesLethargiesLigaseLiverLoxP-flanked alleleMammalsMediatingMedicalMendelian disorderMetabolic PathwayMissionMitochondrial ProteinsMorbidity - disease rateMusMutationN acetyl L glutamateNeonatalNeonatal MortalityNervous System TraumaNeurologicNitrogenOrganPathway interactionsPatientsPeriodicalsPhasePhenotypePlasmaPosturePre-Clinical ModelPrevention strategyProductionProteinsPublic HealthPublishingRegulator GenesRegulatory ElementResearchRiskSeizuresSerotypingSiteSurvivorsTechnologyTestingTherapeuticTransgenesTransgenic MiceTransplantationUnited States National Institutes of HealthUrea cycle disordersViral VectorVulnerable Populationsadeno-associated viral vectorclinical applicationclinical candidateclinical developmentclinical translationcostcritical perioddisabilityeffective therapyenzyme deficiencyexperiencegene productgene replacementgene therapygenetic approachhigh riskhomologous recombinationhuman diseasehumanized mouseimmunosuppressedin vivoliver transplantationliver xenograftmortalitymortality riskmouse modelnatural hypothermianeonatenovelnovel therapeutic interventionnovel therapeuticspostnatal developmentpre-clinicalpre-clinical therapyprogramspromotersevere intellectual disabilitytreatment strategyurea cyclevectorwasting
项目摘要
Project Summary/Abstract The urea cycle is the major pathway for detoxification of ammonia in mammals.
Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a neurologically-devastating condition that, while late-
onset does occur, the disorder primarily is a condition affecting neonates. The deficiency of this enzyme is
characterized clinically by periodic episodes of hyperammonemia resulting in progressive irreversible
neurological injury and severe CNS impairment, particularly during a period of critical postnatal development;
the condition is associated with a high likelihood of early neonatal mortality. The long-term goal of this program
is to develop a clinical candidate gene therapy vector that will result in ammonia control and restore ureagenesis
in CPS1 deficiency. Recent advances in gene therapy have led to the concept of using adeno-associated virus
(AAV)-based biotechnology to treat CPS1 deficiency; at present, this monogenic disorder has no completely
effective therapy except liver transplantation, though often not occurring until the infant has reached a size
where successful transplantation is more likely but multiple episodes of neurological injury have been sustained.
In addition to being one of the most difficult urea cycle disorders to treat clinically, the development of a gene
therapy approach has been hampered by several challenges. First, until recently, there were no animal models
of the disorder. Second, CPS1, the most abundant mitochondrial protein in the human liver, must be expressed
at high level in hepatocytes. And third, the size of the CPS1 cDNA at 4.5kb places limitations on the expression
cassette size; this may be the greatest hindrance for a clinically translatable vector that can be produced at high
titer. This proposal seeks to advance a gene therapy approach using small hepatocyte-specific gene regulatory
elements to produce a compact CPS1-expressing AAV and a hybrid/dual vector AAV as approaches for this
poorly treated disorder. The Lipshutz laboratory recently developed two murine models of CPS1 deficiency and
has published and preliminary data on the efficacy of an AAV approach; this proposal is to complete the
development and bring forth a clinical candidate vector. Preliminary and published data: The research group
has: 1) developed a conditional Cps1-deficient knockout mouse, replicating neonatal onset CPS1 deficiency; 2)
demonstrated hepatocyte-specific expression of CPS1 from single vector AAV that has led to plasma ammonia
control; 3) developed a dual (or split) AAV approach to express CPS1 in the liver; and 4) has produced
humanized mice where CPS1-deficient hepatocytes have repopulated the murine liver; the latter is essential for
testing these vector approaches. Specific Aim 1: Optimize the AAV constructs for hepatic CPS1 expression and
identify the optimal candidate to advance. Specific Aim 2: Test different hepatotropic serotypes of AAV vector-
based CPS1 expression utilizing the optimized transgene cassette in a Cps1-deficient humanized mouse model.
The proposed research is significant as it is expected that at completion a final clinical candidate and serotype
will have been chosen for establishing hepatic gene replacement for CPS1 deficiency.
项目摘要/摘要尿素循环是哺乳动物解毒的主要途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gerald S Lipshutz其他文献
Gerald S Lipshutz的其他文献
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{{ truncateString('Gerald S Lipshutz', 18)}}的其他基金
Gene Therapy Clinical Candidate Development for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症的基因治疗临床候选药物开发
- 批准号:
10339836 - 财政年份:2022
- 资助金额:
$ 42.92万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
10318637 - 财政年份:2019
- 资助金额:
$ 42.92万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
9908195 - 财政年份:2019
- 资助金额:
$ 42.92万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
10540721 - 财政年份:2019
- 资助金额:
$ 42.92万 - 项目类别:
Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency
了解精氨酸酶缺乏的机制并预防独特的神经病理学
- 批准号:
10080755 - 财政年份:2019
- 资助金额:
$ 42.92万 - 项目类别:
Cell and Gene Replacement Strategies for Arginase Deficiency
精氨酸酶缺乏症的细胞和基因替代策略
- 批准号:
10115139 - 财政年份:2017
- 资助金额:
$ 42.92万 - 项目类别:
Cell and Gene Replacement Strategies for Arginase Deficiency
精氨酸酶缺乏症的细胞和基因替代策略
- 批准号:
9289701 - 财政年份:2017
- 资助金额:
$ 42.92万 - 项目类别:
Development of Molecular Therapy for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症分子治疗的进展
- 批准号:
8996735 - 财政年份:2015
- 资助金额:
$ 42.92万 - 项目类别:
Development of Molecular Therapy for Carbamoyl Phosphate Synthetase Deficiency
氨基甲酰磷酸合成酶缺乏症分子治疗的进展
- 批准号:
8872239 - 财政年份:2015
- 资助金额:
$ 42.92万 - 项目类别:
Immunologic Aspects of In Utero or Neonatal AAV-Based Gene Therapy
子宫内或新生儿基于 AAV 的基因治疗的免疫学方面
- 批准号:
8915936 - 财政年份:2014
- 资助金额:
$ 42.92万 - 项目类别:
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