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.

概括 Krabbe病（KD）是由普遍表达的溶酶体酶的缺乏引起的半乳糖基酰胺酶（GALC），该酶负责半乳糖酰亚胺的降解和半乳糖基肾上腺素（Psychosine）。因为在 KD，Psychosine是在Krabbe神经系统中不断产生和积累的。有毒水平 Psychosine被认为是疾病的主要致病触发因素。目前，KD的护理标准是造血干细胞移植（HSCT），仅适用于无症状或早期症状婴儿KD病例，只有持久性疾病。使用腺相关病毒的临床前基因治疗研究（AAV）向量显示出巨大的前景，实际上，AAV基因疗法在生命的早期应用增加了生存，改善生活质量，并降低Twitcher（TWIT）小鼠的神经病理学，KD的自然模型。基于关于这些重要的成功，仅针对婴儿KD开始了基于AAV的基因疗法临床试验。然而，尽管预防了与疾病相关的明显缺陷，HSCT和临床前AAV-GENE 治疗试验表明，神经系统疾病的长期疗效和复兴多样。因此，KD基因治疗的状态，HSCT的局限性主要治疗预症状婴儿 KD以及少年和成人发作KD患者的事实，包括很大一部分Krabbe 患者在很大程度上没有任何治疗，强调需要制定其他策略来维持 KD患者的长期保护。单独或单独或结合当前和新的KD疗法，是实现这一目标的一种潜在方法。在此应用程序中，我们将使用两种小型新化合物，这些化合物有选择地抑制神经酰胺半乳糖基转移酶（CGT）和酸神经酶（ACD），通过神经酰胺和神经酰胺的半乳糖糖基化介导心理剂的酶半乳糖酰胺（ACD）的鞘氨醇（CGT）和脱酰化。基于减少的前提心理综合将在早期产后发育的早期发育中预防/减少与心理相关的病理哺乳动物大脑，我们将测试CGT和ACD的SRT的功效增强HSCT和AAV-GALC基因婴儿KD小鼠模型（Twitcher小鼠）的治疗以及单一治疗的功效在新的成人发病KD模型中，CGT或ACD抑制剂可以改善/预防疾病。