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.

DESCRIPTION (provided by application): 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巨噬细胞（球形细胞）。认知能力下降和运动决定患者通常在五岁之前发生死亡的婴儿的发育。目前在许多州进行了针对Krabbe疾病的新生儿筛查，从而允许治疗具有造血干细胞移植（HPCT）（当前护理标准）的造血干细胞移植（HPCT）。但是，尽管HPCT会导致一些认知的改善，但电动机定义了持久。无法治愈Krabbe疾病。在Twitcher小鼠是Krabbe疾病模型的Twitcher小鼠中的最新研究表明，颅内注射与腺相关病毒（AAV）载体的组合携带了鼠类Galc cdna与HPCT协同植物的野生型副本，以显着改善运动，定义运动时间，生存时间和CNS病理学。尽管在治疗水平上明显有希望，但尚不清楚在Twitcher小鼠中观察到的组合疗法协同作用的机制。我们假设通过HPCT驱动的CNS效应和PNS中AAV介导的基因治疗作用在联合疗法中观察到的协同作用。鼠与人类克拉伯疾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翻译效用。相比之下，狗的自然疾病概括了人类疾病的临床，病理和生化异常。此外，这只狗的大小与婴儿的大小相似，可以评估HPCT和CNS基因转移方法与可用于婴儿的那些相同的狗，以及用于鉴定和验证临床，生化和成像标志物的神经系统疾病严重程度和治疗性有效性的方法，该方法使用用于pediatric诊所中的方法。拟议的研究将有助于确定联合疗法看到的协同作用的机制，并将洞悉疾病发病机理，并有可能确定未来设计其他治疗策略的新途径。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实验疗法的机械作用。