Combination Therapy, Biomarkers, and Imaging in Canine Krabbe Disease

犬克拉伯病的联合治疗、生物标志物和影像学

基本信息

批准号：
9080156
负责人：
CHARLES H VITE
金额：
$ 50.1万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9080156
关键词：
Affect Age Age of Onset Animal Model Biochemical Biochemical Markers Brain Brain Diseases Canis familiaris Cell Death Cells Cessation of life Childhood Clinic Clinical Clinical Markers Cognitive Combined Modality Therapy Complementary DNA Data Dependovirus Deterioration Diffusion Magnetic Resonance Imaging Disease Disease Progression Evaluation Future Galactolipids Gene Transfer Genes Globoid cell leukodystrophy Hematopoietic Stem Cell Transplantation Histologic Human Impaired cognition Infant Infiltration Inherited Injection of therapeutic agent Investigational Therapies Longitudinal Studies Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Mediating Metabolic Methods Modality Modeling Monitor Motor Mus Mutation Myelin Neonatal Screening Nervous system structure Neurodegenerative Disorders Neurologic Dysfunctions Pathogenesis Pathology Pathway interactions Peripheral Nerves Peripheral Nervous System Phase II Clinical Trials Plasma Psychosine Schwann Cells Severities Severity of illness Spectrum Analysis Surrogate Markers Testing Therapeutic Time Tissues Translating Treatment Efficacy Validation adeno-associated viral vector alpha synuclein gene alpha-Mannosidosis base chemokine clinical effect cohort cytokine design disease phenotype effective therapy galactosylceramidase gene therapy human disease imaging biomarker immunoregulation improved insight macrophage motor deficit mouse model nervous system disorder neuroinflammation novel therapeutics oligodendrocyte myelination preclinical study public health relevance standard of care success therapy outcome tissue biomarkers

项目摘要

DESCRIPTION (provided by applicant): Krabbe disease (globoid cell leukodystrophy) is an inherited neurodegenerative disorder caused by mutations in the galactosylceramidase gene (GALC), leading to galactolipid accumulation, abnormal central and peripheral nervous system (CNS and PNS) myelination, oligodendrocyte and Schwann cell death, and the infiltration of multinucleated macrophages (globoid cells). Cognitive decline and motor deterioration develop in affected infants with death commonly occurring before the age of five. Newborn screening for Krabbe disease is currently performed in many states, thereby allowing for treatment of presymptomatic babies with hematopoietic stem-cell transplantation (HPCT), the current standard of care. However, while HPCT results in some cognitive improvement, motor deficits persist. There is no cure for Krabbe disease. Recent studies in the Twitcher mouse, a murine model of Krabbe disease, have shown that a combination of intracranial injection of an adeno-associated virus (AAV) vector carrying a wild type copy of murine GALC cDNA synergizes with HPCT to significantly improve motor deficits, survival time, and CNS pathology. Although clearly promising at a therapeutic level, the mechanisms responsible for the synergy of combination therapy observed in the Twitcher mouse are not understood. We hypothesize that the synergy observed with combination therapy results from HPCT-driven effects in the CNS effects and AAV-mediated gene therapy effects in the PNS. Differences in disease phenotype between murine and human Krabbe disease and the small size of the mouse limit the translational utility of this model. In contrast, naturally-occurring Krabbe disease in dogs recapitulates the clinical, pathological, and biochemical abnormalities of human disease. Additionally, the dog, similar in size to that of an infant, allows for the evaluation of HPCT and CNS gene transfer methods identical to those that can be used in infants, and for the identification and validation of clinicl, biochemical, and imaging markers of nervous system disease severity and therapeutic efficacy using methods that are used in pediatric clinics. The proposed studies will help determine the mechanism of the synergy seen with combination therapy, and will provide insight into disease pathogenesis, potentially identifying new pathways for future design of additional therapeutic strategies. Our lab is uniquely suited to evaluating the mechanistic effects of experimental therapies in large animal models of human nervous system disease.

描述（由申请人提供）：克拉伯病（球状细胞脑白质营养不良）是一种遗传性神经退行性疾病，由半乳糖神经酰胺酶基因（GALC）突变引起，导致半乳糖脂积累、中枢和周围神经系统（CNS 和 PNS）髓鞘形成异常、少突胶质细胞和雪旺细胞死亡，以及多核巨噬细胞（球状细胞）的浸润。认知能力和运动能力下降。受影响的婴儿病情恶化，死亡通常发生在五岁之前。目前许多州都对新生儿进行克拉伯病筛查，从而可以对出现症状的婴儿进行造血干细胞移植（HPCT）（目前的护理标准）进行治疗。然而，虽然 HPCT 可以带来一定的认知改善，但运动缺陷仍然存在。最近对 Twitcher 小鼠（克拉伯病的小鼠模型）的研究表明，克拉伯病的联合作用。颅内注射携带野生型小鼠 GALC cDNA 拷贝的腺相关病毒 (AAV) 载体与 HPCT 协同作用，可显着改善运动缺陷、生存时间和中枢神经系统病理学，尽管在治疗水平上显然有希望，但其机制却是这样的。我们尚不清楚在 Twitcher 小鼠中观察到的联合治疗的协同作用是由 HPCT 驱动的 CNS 效应和 AAV 介导的基因治疗效应引起的。 PNS：小鼠和人类克拉伯病之间的疾病表型差异以及小鼠的小尺寸限制了该模型的转化效用，相反，狗中自然发生的克拉伯病再现了人类疾病的临床、病理和生化异常。此外，狗的大小与婴儿相似，可以评估与可用于婴儿的 HPCT 和 CNS 基因转移方法相同的方法，并用于临床的鉴定和验证，使用儿科诊所使用的方法来确定神经系统疾病严重程度和治疗效果的生化和影像标记，将有助于确定联合治疗的协同作用机制，并将提供对疾病发病机制的深入了解，从而有可能确定新的途径。我们的实验室非常适合评估人类神经系统疾病大型动物模型中实验疗法的机械效应。