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.

概括克拉伯病 (KD) 是由普遍表达的溶酶体酶缺乏引起的半乳糖神经酰胺酶（GALC）负责半乳糖神经酰胺的降解和半乳糖基鞘氨醇（精神鞘氨醇）。因为导致精神碱的合成途径不受影响 KD，精神嘧啶在克拉伯神经系统中不断产生和积累。有毒水平精神氨酸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有症状的患者婴儿 KD 病例且仅是迁延性疾病。使用腺相关病毒进行临床前基因治疗研究 (AAV) 载体已显示出巨大的前景，事实上，在生命早期应用 AAV 基因治疗可以提高生存率，改善 twitcher (twi) 小鼠（川崎病的天然模型）的生活质量并减少神经病理学。基于基于这些重要的成功，基于 AAV 的基因治疗临床试验正在启动，仅针对婴儿 KD。然而，尽管 HSCT 和临床前 AAV 基因可以预防重大的疾病相关缺陷，治疗试验显示出不同的长期疗效和神经系统疾病的复发。因此，KD 基因治疗的现状、HSCT 主要治疗症状前婴儿的局限性川崎病以及青少年和成人发病的川崎病患者（其中大部分是克拉伯病患者）这一事实患者大多没有接受任何治疗，强调需要制定额外的策略来维持为 KD 患者提供长期保护。单独使用底物减少疗法（SRT）策略或与当前和新的 KD 疗法相结合，是实现这一目标的一种潜在方法。在这个应用程序中我们将使用两种小新化合物，选择性抑制神经酰胺半乳糖基转移酶（CGT）和酸神经酰胺酶（ACD），通过神经酰胺的半乳糖基化介导精神氨酸产生的酶，鞘氨醇（CGT）和半乳糖神经酰胺（ACD）的脱酰化。在减少的前提下精神分裂症合成将预防/减少出生后早期发育时精神分裂症相关的病理学哺乳动物大脑，我们将测试CGT和ACD的SRT增强HSCT和AAV-GALC基因的功效婴儿 KD 小鼠模型（抽搐小鼠）的治疗以及单一治疗的疗效 CGT 或 ACD 抑制剂可改善/预防新的成人发病 KD 模型中的疾病。