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Translational studies on cerebrospinal fluid (CSF)-directed gene therapy for global neurometabolic brain disease

脑脊液（CSF）定向基因治疗全球神经代谢性脑疾病的转化研究

基本信息

批准号：
9893931
负责人：
JOHN H WOLFE
金额：
$ 67.49万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893931
关键词：
Address Adverse event Affect Alpha-mannosidase Animal Diseases Animal Model Animals Autopsy Bathing Brain Brain Diseases Brain imaging Cell Transplantation Cells Cerebral Dominance Cerebral Ventricles Cerebrospinal Fluid Clinical Clinical Trials Complementary DNA Defect Development Diffusion Magnetic Resonance Imaging Disease Disease Marker Disease Progression Disease model Dose Effectiveness Endosomes Enzymes Extracellular Space Family Felidae Felis catus Gene Delivery Gene Proteins Gene Transduction Agent Gene therapy trial Genes Genetic Hereditary Disease Histologic Human Imaging Techniques Immune response Infusion procedures Injections Investigational Therapies Laboratory Study Lesion Liquid substance Longevity Lysosomal Storage Diseases Lysosomes Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Mannose Measurement Mediating Mendelian disorder Metabolic Methods Modeling Monitor Mutation Neuraxis Neurologic Oligosaccharides Organ Transplantation Pathology Patients Protocols documentation Recovery Resolution Rodent Route Serum Severity of illness Structural Genes Structure Testing Translating Translations Vertebral column adeno-associated viral vector advanced disease alpha-Mannosidosis base brain cell brain size cellular transduction cisterna magna comparative effective therapy effectiveness evaluation enzyme replacement therapy enzyme structure gene correction gene product gene therapy gray matter human disease human model improved lateral ventricle mutant nervous system disorder non-invasive imaging receptor mediated endocytosis response translational model translational study treatment response treatment strategy vector white matter

项目摘要

ABSTRACT A major barrier to effective treatment of the central nervous system (CNS) in most inherited diseases is that pathology is present throughout the brain because the metabolic defect is present in most brain cells. Thus, global distribution of the gene or gene product is required. Several gene therapy strategies are being investigated for treatment of global brain lesions. However, all of the approaches have significant shortcomings, which become apparent in large animal models of human diseases. Development of more effective treatments in these models will facilitate translation into clinical usage. This project will investigate AAV vector mediated gene delivery into the brain by infusion into the cerebrospinal fluid (CSF), which can result in disseminated delivery of a gene in a large animal brain. The disease model to be evaluated is alpha-mannosidosis (AMD) in the cat, a lysosomal storage disorder (LSD) caused by mutations in the lysosomal enzyme (LE) structural gene, alpha-mannosidase (MANB). The strategy for treatment is based on cross-correction, in which transfer of a normal copy of the MANB cDNA into AMD cells results in the metabolic correction of those gene-transduced cells. Furthermore, the genetically corrected cells release normal MANB enzyme, which is taken up by surrounding cells and corrects them metabolically as well. This well-established cross-correction mechanism is the basis for treatments of most LSDs. The disease progression and improvement from treatment will be monitored in living animals by clinical neurological assessment, life-span increases, serum and CSF analyses, and non-invasive brain imaging by magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI). In post-mortem animals, the disease correction will be analyzed quantitatively for distribution of vector transduction, increases in MANB enzymatic activity, reduction of mannose-containing oligosaccharide substrate accumulation, histopathological changes, and potential adverse host responses. We will address important issues affecting translation by investigating strategies to attain more complete correction of the brain: in Aim 1 we will investigate the effects of alternative routes of CSF delivery; in Aim 2 we will investigate the effects of dose escalation on the extent of resolution of pathology; and in Aim 3 we will determine the effectiveness of therapy when initiated at progressively more severe stages of disease to evaluate the potential to ameliorate advanced disease.

摘要