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

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Ernesto Roque Bongarzone其他文献

Ernesto Roque Bongarzone的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Ernesto Roque Bongarzone', 18)}}的其他基金

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
  • 批准号:
    10708106
  • 财政年份:
    2022
  • 资助金额:
    $ 60.66万
  • 项目类别:
Therapies to Stimulate Remyelination
刺激髓鞘再生的疗法
  • 批准号:
    8821792
  • 财政年份:
    2014
  • 资助金额:
    $ 60.66万
  • 项目类别:
Therapies to Stimulate Remyelination
刺激髓鞘再生的疗法
  • 批准号:
    8935960
  • 财政年份:
    2014
  • 资助金额:
    $ 60.66万
  • 项目类别:
Combined Neuroprotection and Metabolic Correction to Treat Leukodystrophies
联合神经保护和代谢校正治疗脑白质营养不良
  • 批准号:
    9333446
  • 财政年份:
    2009
  • 资助金额:
    $ 60.66万
  • 项目类别:
Combined neuroprotection and metabolic correction to treat leukodystrophies
联合神经保护和代谢校正治疗脑白质营养不良
  • 批准号:
    8321032
  • 财政年份:
    2009
  • 资助金额:
    $ 60.66万
  • 项目类别:
Combined neuroprotection and metabolic correction to treat leukodystrophies
联合神经保护和代谢校正治疗脑白质营养不良
  • 批准号:
    8525467
  • 财政年份:
    2009
  • 资助金额:
    $ 60.66万
  • 项目类别:
Combined neuroprotection and metabolic correction to treat leukodystrophies
联合神经保护和代谢校正治疗脑白质营养不良
  • 批准号:
    7792796
  • 财政年份:
    2009
  • 资助金额:
    $ 60.66万
  • 项目类别:
Combined Neuroprotection and Metabolic Correction to Treat Leukodystrophies
联合神经保护和代谢校正治疗脑白质营养不良
  • 批准号:
    9028056
  • 财政年份:
    2009
  • 资助金额:
    $ 60.66万
  • 项目类别:
Combined neuroprotection and metabolic correction to treat leukodystrophies
联合神经保护和代谢校正治疗脑白质营养不良
  • 批准号:
    8131096
  • 财政年份:
    2009
  • 资助金额:
    $ 60.66万
  • 项目类别:

相似海外基金

Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The impact of changes in social determinants of health on adolescent and young adult mental health during the COVID-19 pandemic: A longitudinal study of the Asenze cohort in South Africa
COVID-19 大流行期间健康社会决定因素的变化对青少年和年轻人心理健康的影响:南非 Asenze 队列的纵向研究
  • 批准号:
    10755168
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
A Priority Setting Partnership to Establish a Patient, Caregiver, and Clinician-identified Research Agenda for Adolescent and Young Adult Cancer in Canada
建立优先合作伙伴关系,以建立患者、护理人员和临床医生确定的加拿大青少年和年轻人癌症研究议程
  • 批准号:
    480840
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
    Miscellaneous Programs
Incidence and Time on Onset of Cardiovascular Risk Factors and Cardiovascular Disease in Adult Survivors of Adolescent and Young Adult Cancer and Association with Exercise
青少年和青年癌症成年幸存者心血管危险因素和心血管疾病的发病率和时间以及与运动的关系
  • 批准号:
    10678157
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
Fertility experiences among ethnically diverse adolescent and young adult cancer survivors: A population-based study
不同种族青少年和年轻成年癌症幸存者的生育经历:一项基于人群的研究
  • 批准号:
    10744412
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
Treatment development for refractory leukemia using childhood/adolescent, and young adult leukemia biobank
利用儿童/青少年和青年白血病生物库开发难治性白血病的治疗方法
  • 批准号:
    23K07305
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular design of Two-Way Player CAR-T cells to overcome disease/antigen heterogeneity of childhood, adolescent, and young adult cancers
双向 CAR-T 细胞的分子设计,以克服儿童、青少年和年轻成人癌症的疾病/抗原异质性
  • 批准号:
    23H02874
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Effects of adolescent social isolation on adult decision making and corticostriatal circuitry
青少年社会隔离对成人决策和皮质纹状体回路的影响
  • 批准号:
    10756652
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
Adolescent trauma produces enduring disruptions in sleep architecture that lead to increased risk for adult mental illness
青少年创伤会对睡眠结构产生持久的破坏,从而导致成人精神疾病的风险增加
  • 批准号:
    10730872
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
Using Tailored mHealth Strategies to Promote Weight Management among Adolescent and Young Adult Cancer Survivors
使用量身定制的移动健康策略促进青少年和年轻癌症幸存者的体重管理
  • 批准号:
    10650648
  • 财政年份:
    2023
  • 资助金额:
    $ 60.66万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了