权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel Gene Therapy Strategies for Canavan Disease

卡纳万病的新基因治疗策略

基本信息

批准号：
10561698
负责人：
Guangping Gao
金额：
$ 42.24万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10561698
关键词：
Acetyltransferase Adverse effects Age Animals Aspartoacylase Astrocytes Behavioral Bioinformatics Brain Brain region Canavan Disease Cell Line Cells Central Nervous System Cessation of life Chickens Childhood Clinical DNA cassette Data Defect Disease Dose Elements Energy Metabolism Engineering Ensure Epigenetic Process Etiology Functional disorder Funding Genes Goals Head Homeostasis Human Impaired cognition Impairment In Vitro Investigation Knockout Mice Knowledge Life Long-Term Effects Macaca fascicularis Macrocephaly Mediating Metabolic Metabolism Microscopic Mitochondria Modeling Morphology Motor Mus Muscle hypotonia Mutation N-acetylaspartate N-acetylaspartic acid Neonatal Neurodegenerative Disorders Neurologic Neurons Oligodendroglia Organ Patients Peripheral Phenotype Physiological Prevention Psychomotor Performance Recombinant adeno-associated virus (rAAV)Research Role Safety Seizures Shapes Swelling Testing Therapeutic Tissues Toxic effect Transgenes Translations Urine Viral Packaging adverse outcome autosome beta Actin cell type clinical application clinically relevant design disease phenotype gene replacement therapy gene therapy improved in vivo intravenous injection leukodystrophy loss of function mutation metabolome mouse model neuroimaging neuropathology nonhuman primate novel overexpression pre-clinical preclinical study promoter side effect theories treatment strategy vector white matter

项目摘要

ABSTRACT Canavan disease (CD) is a rare childhood leukodystrophy caused by autosomal recessive mutations in the aspartoacylase (ASPA) gene. Deficiency of ASPA in Canavan patients leads to the accumulation of N- Acetyl-Aspartic Acid (NAA), resulting in swelling and spongy degeneration of white matter in the brain. The clinical manifestations of this fatal disease include psychomotor retardation, muscular hypotonia, macrocephaly, head lag, seizures, and early death. Synthesis of NAA is carried out in the mitochondria of neurons by N-acetyltransferase-8-like (NAT8L) and hydrolyzed in oligodendrocytes by ASPA. Gene replacement therapy for ASPA deficiency is currently the most promising strategy for treating CD. Notably, we have recently achieved full therapeutic correction of the Canavan phenotype in the Aspa knockout (CD-KO) mouse model. A single intravenous injection of recombinant adeno-associated virus packaged with the human ASPA transgene (rAAV-hASPA) at early ages completely resolves neuropathology, resulting in treated animals that outperform wild-types in motor function tests. However, based on strong preliminary evidence, we now hypothesize that the CD phenotype presents a secondary etiology related to metabolism dysfunction. In addition, we recently revealed that overexpression of ASPA in wild type cells in vitro resulted in abnormal mitochondrial shape and function. These findings necessitate further preclinical investigations that focus on: 1) characterizing the possible toxicity of ASPA overexpression in cell types of the CNS and peripheral organs, 2) developing ASPA regulatory cassette(s) that can mimic endogenous physiological levels of ASPA to circumvent adverse effects that may exist due to treatment, and 3) determining the physiological and behavioral effects of ASPA overexpression using a clinically relevant non-human primate model. Our new research strategy now builds on our current promising progress and advances our goals for a safe and effective gene therapy for CD.

摘要 Canavan病（CD）是一种罕见的儿童脑白质营养不良，由常染色体隐性突变引起，乙酰化酶（ASPA）基因。Canavan患者缺乏ASPA导致N- 乙酰天冬氨酸（NAA），导致脑内白色物质肿胀和海绵状变性。的这种致命疾病的临床表现包括精神发育迟滞，肌肉张力减退，大头畸形头迟滞癫痫和早逝NAA的合成在线粒体中进行，神经元通过N-乙酰转移酶-8-样（NAT 8L）和ASPA水解少突胶质细胞。基因 ASPA缺乏的替代疗法是目前治疗CD最有希望的策略。值得注意的是，最近在Aspa敲除（CD-KO）中实现了Canavan表型的完全治疗纠正小鼠模型单次静脉注射重组腺相关病毒包装的人 ASPA转基因（rAAV-hASPA）在早期完全解决了神经病理学，在运动功能测试中表现优于野生型。然而，基于强有力的初步证据，假设CD表型是与代谢功能障碍相关的次要病因。在此外，我们最近发现ASPA在体外野生型细胞中的过表达导致了异常的细胞凋亡。线粒体的形状和功能。这些发现需要进一步的临床前研究，重点是：1）表征ASPA过表达在CNS和外周器官的细胞类型中的可能毒性，2）开发能够模拟ASPA的内源生理水平的ASPA调节盒，避免由于治疗而可能存在的副作用，以及3）确定生理和使用临床相关的非人灵长类动物模型研究ASPA过表达的行为效应。我们的新研究战略现在建立在我们目前有希望的进展和推进我们的目标，为一个安全，有效基因治疗CD。

项目成果

期刊论文数量（111）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retinal gene delivery by rAAV and DNA electroporation.

DOI：
10.1002/9780471729259.mc14d04s28
发表时间：
2013
期刊：
Current protocols in microbiology
影响因子：
0
作者：
Venkatesh, Aditya;Ma, Shan;Langellotto, Fernanda;Gao, Guangping;Punzo, Claudio
通讯作者：
Punzo, Claudio

Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival.

DICER表达对于成年中脑多巴胺能神经元维持和生存至关重要。

DOI：
10.1016/j.mcn.2013.10.009
发表时间：
2014-01
期刊：
Molecular and cellular neurosciences
影响因子：
0
作者：
Pang X;Hogan EM;Casserly A;Gao G;Gardner PD;Tapper AR
通讯作者：
Tapper AR

Querying Recombination Junctions of Replication-Competent Adeno-Associated Viruses in Gene Therapy Vector Preparations with Single Molecule, Real-Time Sequencing.

DOI：
10.3390/v15061228
发表时间：
2023-05-24
期刊：
Viruses
影响因子：
0
作者：
Yip M;Chen J;Zhi Y;Tran NT;Namkung S;Pastor E;Gao G;Tai PWL
通讯作者：
Tai PWL

H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.

DOI：
10.1172/jci154229
发表时间：
2022-11-15
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Haase, Santiago;Banerjee, Kaushik;Mujeeb, Anzar A.;Hartlage, Carson S.;Nunez, Fernando M.;Nunez, Felipe J.;Alghamri, Mahmoud S.;Kadiyala, Padma;Carney, Stephen;Barissi, Marcus N.;Taher, Ayman W.;Brumley, Emily K.;Thompson, Sarah;Dreyer, Justin T.;Alindogan, Caitlin T.;Garcia-Fabiani, Maria B.;Comba, Andrea;Venneti, Sriram;Ravikumar, Visweswaran;Koschmann, Carl;Carcaboso, Angel M.;Vinci, Maria;Rao, Arvind;Yu, Jennifer S.;Lowenstein, Pedro R.;Castro, Maria G.
通讯作者：
Castro, Maria G.

Native Chromatin Immunoprecipitation Using Murine Brain Tumor Neurospheres.