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CGT and ACD Inhibitors for SRT Treatment of Krabbe Disease

CGT 和 ACD 抑制剂用于 SRT 治疗克拉伯病

基本信息

批准号：
10581356
负责人：
Ernesto Roque Bongarzone
金额：
$ 60.66万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581356
关键词：
Address Adolescent Adult Affect Aftercare Age Age of Onset Age-Months Animal Disease Models BRAIN initiative Birth Brain Cells Ceramides Child Clinical Clinical Data Clinical Trials Cognitive deficits Collaborations Combined Modality Therapy Complement Cycloserine Development Disease Engraftment Enzymes Galactosylceramides Galactosyltransferases Gene therapy trial Gliosis Globoid cell leukodystrophy Goals Hematopoietic Stem Cell Transplantation Human Infant Infantile Globoid Cell Leukodystrophy Knowledge Life Life Expectancy Lipoidosis Longevity Lysosomal Storage Diseases Measurable Mediating Mission Modeling Morbidity - disease rate Mus Mutation Myelin National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke Neonatal Nervous system structure Neurologic Neurons Outcome Pathogenicity Pathology Pathway interactions Patients Pharmacologic Substance Phenotype Prevention Production Psychosine Public Health Quality of life Recurrent disease Research Risk Safety Serine Sphingosine Testing Time Transferase Transplantation Treatment Efficacy United States National Institutes of Health Viral Viral Genes Work adeno-associated viral vector aged base canine model deacylation efficacy testing galactosylceramidase galactosylgalactosylglucosylceramidase gene therapy gene therapy clinical study gene therapy clinical trial improved inhibitor inhibitor therapy irradiation leukodystrophy mortality motor deficit mouse model nervous system disorder neuroinflammation neuropathology new combination therapies novel therapeutics postnatal postnatal development pre-clinical preconditioning prevent side effect standard of care success transplant model transplantation therapy

项目摘要

SUMMARY Krabbe disease (KD) is caused by the deficiency of the ubiquitously expressed lysosomal enzyme galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and galactosylsphingosine (psychosine). Because the synthetic pathway conducing to psychosine is not affected in KD, psychosine is continuously produced and accumulated in the Krabbe nervous system. Toxic levels of psychosine are considered the main pathogenic trigger of disease. Currently, the standard of care for KD is hematopoietic stem cell transplantation (HSCT), which is only applicable to asymptomatic or early symptomatic infantile KD cases and only protracts disease. Pre-clinical gene therapy studies using adeno-associated viral (AAV) vectors have shown great promise and in fact, AAV gene therapy applied early in life increases survival, improves quality of life, and decreases neuropathology in twitcher (twi) mice, the natural model for KD. Based on these important successes, AAV-based gene therapy clinical trials are being started only for infantile KD. However, despite the prevention of significant disease-related deficits, HSCT and pre-clinical AAV-gene therapy trials show varied long-term efficacy and resurgence of neurological disease. Thus, the status of gene therapy for KD, the limitations of HSCT to treat primarily presymptomatic infantile KD and the fact that juvenile and adult onset KD patients, which encompass a significant fraction of Krabbe patients, largely remain without any treatment, highlight the need to develop additional strategies to sustain long-term protection for KD patients. The use of substrate reduction therapies (SRT) strategies, singly or combined with current and new therapies for KD, is one potential way to achieve this. In this application we will use two small new compounds which selectively inhibit ceramide galactosyltransferase (CGT) and acid ceramidase (ACD), enzymes that mediate the production of psychosine via galactosylation of ceramides and sphingosine (CGT) and deacylation of galactosylceramide (ACD). Based on the premise that reducing psychosine synthesis will prevent/reduce psychosine-related pathology at early postnatal development of the mammalian brain, we will test the efficacy of SRT of CGT and ACD to enhance HSCT and AAV-GALC gene therapy in the mouse model of infantile KD (twitcher mouse) and the efficacy of single treatment with CGT or ACD inhibitors to ameliorate/prevent disease in a new model of adult-onset KD.

总结