Protein Tranduction for Treatment of Krabbe Disease

治疗克拉伯病的蛋白质转导

• 批准号: 6522014
• 负责人: CHRISTOPHER B ECKMAN
• 金额: $ 18.64万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522014
• 关键词: Krabbe's disease; autosomal recessive trait; blood brain barrier; brain; chimeric proteins; confocal scanning microscopy; disease /disorder model; enzyme activity; enzyme therapy; fluorescence microscopy; gene expression; gene mutation; molecular cloning; myelinopathy; nonhuman therapy evaluation; polymerase chain reaction; protein transport

DESCRIPTION (provided by applicant): Krabbe disease is a degenerative neurological disorder primarily affecting infants and young children although rare cases of adult onset have been described. Affected individuals typically present with symptoms in the first few months of life. Disease progression is generally rapid, leading to death within 1-2 years. The disease is inherited as an autosomal recessive trait caused by mutations in the galactocerebrosidase (GALC) gene that severely affect the activity of the enzyme. Obvious therapeutic approaches include delivery of active GALC enzyme to the brain through either gene or protein therapy. While significant advances have been made in gene therapy over the years, stable expression of proteins in the brain has not yet been achieved. Enzyme replacement therapy offers another possible therapeutic approach and has been shown to be safe and effective for the treatment of peripheral clinical manifestations in another lysosomal storage disorder, Type I Gaucher's disease. For diseases such as Krabbe disease, however, the therapeutic enzyme must be delivered to the brain to have a significant clinical impact. Recently, Steven Dowdy and colleagues have made a significant advance in the delivery of macromolecules to the brain (Schwarze et al., 1999). They have shown that that even very large proteins can cross the blood-brain barrier to enter into the brain in biologically active form when coupled to an 11 amino acids protein transduction domain derived from the IRV TAT protein. In this application we propose experiments to generate TAT PTD/GALC fusion proteins and examine whether these will get to the brain and restore normal function and enhance survivability in an animal model of Krabbe disease. The lessons learned from these experiments may be useful for other diseases where delivery of a therapeutic protein may be desired, such as Alzheimer's disease and Parkinson's.

描述（由申请人提供）：