Gene Therapy for Neurodegenerative Lysosomal Storage Diseases

神经退行性溶酶体贮积病的基因治疗

• 批准号: 8437280
• 负责人: MIGUEL S ESTEVES
• 金额: $ 49.31万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437280
• 关键词: 2 year old; Adolescent; Adult; Age of Onset; Age-Months; Animal Model; Animals; Behavioral; Biochemical; Biological Assay; Brain; Capsid; Cells; Cerebellar Nuclei; Cerebrospinal Fluid; Childhood; Clinical; Clinical Trials; Clinical assessments; Complementary DNA; Complex; DNA Shuffling; Development; Disease; Disease Progression; Dose; Effectiveness; Elderly; Ensure; Enzymes; Family Felidae; Felis catus; Frequencies; Functional disorder; Future; Ganglioside GM1; Gangliosidosis GM1; Gene Delivery; Gene Transfer; Generations; Genes; Goals; Health; Human; Infant; Infusion procedures; Knockout Mice; Libraries; Live Birth; Longitudinal Studies; Lung; Lysosomal Storage Diseases; Lysosomes; Magnetic Resonance Imaging; Mediating; Methodology; Modality; Modeling; Modern Medicine; Molecular Evolution; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurologic; Neurons; Neurosciences; Organ; Outcome; Patients; Peripheral; Phase; Process; Serotyping; Severity of illness; Single-Gene Defect; Spinal Cord; Staging; Surface; Testing; Thalamic structure; Therapeutic; Therapeutic Studies; Time; Treatment Efficacy; Tropism; Tyrosine; Validation; acid beta-galactosidase; adeno-associated viral vector; base; beta-Galactosidase; brain size; design; effective therapy; efficacy testing; gene therapy; in vivo; infancy; lateral ventricle; meetings; minimally invasive; mouse model; mutant; nervous system disorder; neurochemistry; novel strategies; research study; therapeutic effectiveness; transduction efficiency; treatment strategy; vector

DESCRIPTION (Provided by Applicant): Lysosomal storage diseases (LSDs) are single gene defects that result in the deficiency of a catabolic lysosomal enzyme and accumulation of one or more of its macromolecular substrates in the lysosome. GM1 gangliosidosis results from deficiency of the lysosomal enzyme beta-galactosidase (betagal), leading to progressive and fatal neurodegeneration. Human GM1 gangliosidosis occurs as three types based on disease severity and age of onset, classified as infantile, juvenile, and adult-onset forms. Gene therapy with adeno-associated viral vectors is a very promising strategy for treatment of GM1 gangliosidosis based on extraordinary preliminary results in the knockout mouse model. However, the mouse brain is 1,000-2,000 times smaller and much less complex than the brain of a human infant, requiring that results obtained in mice be reproduced in an animal with a brain size and complexity more similar to humans. The well-characterized feline model of GM1 gangliosidosis, with a brain size only 15 times smaller than a human infant, will be utilized to test therapeutic efficacy of AAV vectors in a larger and more complex brain. In addition, preliminary mouse studies employed a mouse beta-galactosidase cDNA, although AAV vectors for human clinical trials will express human betagal. Therefore, it is necessary to perform bio-equivalency studies to ensure the functionality of the human betagal cDNA before initiating human clinical trials. The experiments in this application are designed to advance AAV gene therapy toward human clinical trials through the following specific aims. In Aim 1, short-term therapeutic studies will be performed after intraparenchymal or CSF-mediated delivery of AAV vectors to the feline GM1 brain. Also, a direct comparison of human and mouse betagal will be conducted in short-term experiments in GM1 mice. In Aim 2 long-term studies of therapeutic efficacy in GM1 cats and mice will be conducted using clinical, behavioral, and biochemical assays of disease progression. Finally, Aim 3 will test the principle of in vivo selection of an AAV capsid library (molecular evolution) to identify AAV vectors with tropism for the GM1 mouse central nervous system (CNS) after intravascular (iv) infusion, and then test their therapeutic efficacy in these mice. Validation of this approach to generate AAV vectors with CNS-tropism after iv infusion will pave the way for development of such vectors for human application.

描述（由申请人提供）：溶酶体胆积病（LSD）是单基因缺陷，其导致分解代谢溶酶体酶的缺乏和一种或多种其大分子底物在溶酶体中的积累。GM 1神经节苷脂沉积症是由于溶酶体酶β-半乳糖苷酶（β-galactosidase，β-galactosidase，β-galactosidase）缺乏引起的，导致进行性和致命性神经变性。人类GM 1神经节苷脂沉积症根据疾病严重程度和发病年龄分为三种类型，分为婴儿型、青少年型和成人型。腺相关病毒载体的基因治疗是一个非常有前途的策略，用于治疗GM 1神经节苷脂沉积症的基础上，在敲除小鼠模型的非凡的初步结果。然而，小鼠的大脑比人类婴儿的大脑小1，000 - 2，000倍，复杂性也低得多，因此需要在小鼠中获得的结果在具有与人类更相似的大脑大小和复杂性的动物中重现。脑大小仅比人类婴儿小15倍的GM 1神经节苷脂沉积症的良好表征的猫模型将用于测试AAV载体在更大和更复杂的脑中的治疗功效。此外，初步的小鼠研究采用小鼠β-半乳糖苷酶cDNA，尽管用于人临床试验的AAV载体将表达人β 1。因此，有必要在启动人体临床试验之前进行生物等效性研究，以确保人β 1 cDNA的功能性。本申请中的实验旨在通过以下特定目的将AAV基因治疗推向人类临床试验。在目的1中，将在脑实质内或CSF介导的AAV载体递送至猫GM 1脑后进行短期治疗研究。此外，将在GM 1小鼠的短期实验中对人和小鼠β 1进行直接比较。在目标2中，将使用疾病进展的临床、行为和生化测定在GM 1猫和小鼠中进行治疗有效性的长期研究。最后，目标3将测试AAV衣壳文库的体内选择（分子进化）的原理，以鉴定在血管内（iv）输注后对GM 1小鼠中枢神经系统（CNS）具有嗜性的AAV载体，然后测试它们在这些小鼠中的治疗功效。验证这种方法以在静脉输注后产生具有CNS向性的AAV载体将为开发用于人类应用的此类载体铺平道路。

项目成果

Sustained normalization of neurological disease after intracranial gene therapy in a feline model.

• DOI: 10.1126/scitranslmed.3007733
• 发表时间: 2014-04-09
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: McCurdy VJ;Johnson AK;Gray-Edwards HL;Randle AN;Brunson BL;Morrison NE;Salibi N;Johnson JA;Hwang M;Beyers RJ;Leroy SG;Maitland S;Denney TS;Cox NR;Baker HJ;Sena-Esteves M;Martin DR
• 通讯作者: Martin DR

Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy.

• DOI: 10.1016/j.omtm.2017.07.005
• 发表时间: 2017-09-15
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Gray-Edwards HL;Jiang X;Randle AN;Taylor AR;Voss TL;Johnson AK;McCurdy VJ;Sena-Esteves M;Ory DS;Martin DR
• 通讯作者: Martin DR