JPND - Multicellular organoids: modeling, mechanisms and therapy development for C9ORF72-associated neurodegeneration.

JPND - 多细胞类器官:C9ORF72 相关神经变性的建模、机制和治疗开发。

基本信息

  • 批准号:
    MR/V000470/1
  • 负责人:
  • 金额:
    $ 54.98万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2020
  • 资助国家:
    英国
  • 起止时间:
    2020 至 无数据
  • 项目状态:
    已结题

项目摘要

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating disorders. The most genetic cause of ALS and FTD is linked to mutations in C9ORF72 gene. While significant discoveries have recently been made in the genetics of ALS/FTD, patients still have no real therapeutic treatments. The lack of any cure for ALS-linked C9ORF72 is attributable primarily to: (i) Poor understanding of the molecular pathogenesis of neurodegeneration; (ii) Lack of reliable animal models mimicking the multicellular and multi-mechanism complexity of the human disease; (iii) Delivery of therapeutically attractive molecules has been hampered by inefficient delivery methods including factors like the blood-brain barrier; (iv) Ineffective targeting of therapeutic agents specifically to the diseased sites of the brain and spinal cord. Research efforts aimed at understanding how mutations in ALS causative genes leads to motor neuron injury are of the utmost importance to enable therapeutic development for these disorders. The limitations associated with existing C9orf72 models can be overcome by using specific patient cells - derived 3D models named organoids. Thus, organoids provide unique opportunities as a system for the development of pharmacological or tailored gene therapies for C9ORF72-linked neuronal injury. Here, we assembled a multidisciplinary research team with complimentary expertise to examine strategies to overcome some of these challenges. The overall aims of our research programme are: (1) Generate 3D in vitro multicellular organoids models from iPSCs derived from healthy and patients with C9ORF72 ALS/FTD; (2) Fully characterise the newly generated models using established assays in the consortium (e.g. molecular markers and electrophysiology); (3) Explore how neuronal injury happen in ALS; (4) develop treatment for C9orf72 linked ALS..
肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)是毁灭性的疾病。ALS和FTD的最大遗传原因与C9ORF72基因突变有关。虽然最近在ALS/FTD的遗传学方面取得了重大发现,但患者仍然没有真正的治疗方法。未能治愈与肌萎缩侧索硬化症相关的C9ORF72主要是由于:(I)对神经退行性变的分子发病机制缺乏了解;(Ii)缺乏模拟人类疾病多细胞和多机制复杂性的可靠动物模型;(Iii)由于输送方法低效,包括血脑屏障等因素,阻碍了具有治疗吸引力的分子的输送;(Iv)针对大脑和脊髓病变部位的治疗剂靶向无效。旨在了解肌萎缩侧索硬化症致病基因突变如何导致运动神经元损伤的研究努力,对于开发这些疾病的治疗方法至关重要。与现有C9orf72模型相关的限制可以通过使用特定的患者细胞衍生的名为有机化合物的3D模型来克服。因此,有机化合物作为一种系统,为开发C9ORF72相关神经元损伤的药物或定制基因疗法提供了独特的机会。在这里,我们召集了一个拥有互补专业知识的多学科研究团队,以审查克服其中一些挑战的战略。我们研究计划的总体目标是:(1)从健康人和C9ORF72 ALS/FTD患者的IPSCs中建立3D多细胞有机体模型;(2)利用该联盟已建立的分析方法(如分子标记和电生理学)充分表征新生成的模型;(3)探索ALS中神经元损伤的发生机制;(4)开发C9orf72连锁ALS的治疗方法。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.
C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.
  • DOI:
    10.26508/lsa.202101276
  • 发表时间:
    2022-09
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Marchi, Paolo M.;Marrone, Lara;Brasseur, Laurent;Coens, Audrey;Webster, Christopher P.;Bousset, Luc;Destro, Marco;Smith, Emma F.;Walther, Christa G.;Alfred, Victor;Marroccella, Raffaele;Graves, Emily J.;Robinson, Darren;Shaw, Allan C.;Wan, Lai Mei;Grierson, Andrew J.;Ebbens, Stephen J.;De Vos, Kurt J.;Hautbergue, Guillaume M.;Ferraiuolo, Laura;Melki, Ronald;Azzouz, Mimoun
  • 通讯作者:
    Azzouz, Mimoun
Towards 3D Bioprinted Spinal Cord Organoids.
Delivery of therapeutic AAV9 vectors via cisterna magna to treat neurological disorders.
通过小脑延髓池递送治疗性 AAV9 载体以治疗神经系统疾病。
  • DOI:
    10.1016/j.molmed.2021.09.007
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
    Marchi PM
  • 通讯作者:
    Marchi PM
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Mimoun Azzouz其他文献

Therapeutic gene silencing in neurological disorders, using interfering RNA
  • DOI:
    10.1007/s00109-005-0649-1
  • 发表时间:
    2005-03-10
  • 期刊:
  • 影响因子:
    4.200
  • 作者:
    G. Scott Ralph;Nicholas D. Mazarakis;Mimoun Azzouz
  • 通讯作者:
    Mimoun Azzouz
A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders
对AAV基因疗法用于单基因疾病的免疫抑制方案的系统评价
  • DOI:
    10.1016/j.ymthe.2024.07.016
  • 发表时间:
    2024-10-02
  • 期刊:
  • 影响因子:
    12.000
  • 作者:
    Besarte Vrellaku;Ilda Sethw Hassan;Rebecca Howitt;Christopher P. Webster;Eli Harriss;Fraser McBlane;Corinne Betts;Jorge Schettini;Mattia Lion;John E. Mindur;Michael Duerr;Pamela J. Shaw;Janine Kirby;Mimoun Azzouz;Laurent Servais
  • 通讯作者:
    Laurent Servais
Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo
mRNA 输出介质 Gle1 的缺陷会损害斑马鱼胚胎中雪旺细胞的发育
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    A. Şeytanoğlu;N. Alsomali;C. F. Valori;Alan T. McGown;H. Kim;Ke Ning;T. Ramesh;Basil Sharrack;Basil Sharrack;Jonathan D. Wood;Mimoun Azzouz;Mimoun Azzouz
  • 通讯作者:
    Mimoun Azzouz
Prospects for gene replacement therapies in amyotrophic lateral sclerosis
肌萎缩侧索硬化症基因替代疗法的前景
  • DOI:
    10.1038/s41582-022-00751-5
  • 发表时间:
    2022-12-08
  • 期刊:
  • 影响因子:
    33.100
  • 作者:
    Ilaria Giovannelli;Adrian Higginbottom;Janine Kirby;Mimoun Azzouz;Pamela J. Shaw
  • 通讯作者:
    Pamela J. Shaw

Mimoun Azzouz的其他文献

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{{ truncateString('Mimoun Azzouz', 18)}}的其他基金

University of Sheffield Advanced Cell and Gene Therapies MSc
谢菲尔德大学高级细胞和基因疗法理学硕士
  • 批准号:
    MC_PC_22001
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
    Intramural
University of Sheffield Advanced Cell and Gene Therapies MSc Bursaries
谢菲尔德大学高级细胞和基因疗法理学硕士助学金
  • 批准号:
    MC_PC_22009
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
    Intramural
Gene Therapy Innovation and Manufacturing Centre (GTIMC)
基因治疗创新与制造中心(GTIMC)
  • 批准号:
    MR/V030140/1
  • 财政年份:
    2021
  • 资助金额:
    $ 54.98万
  • 项目类别:
    Research Grant
SMN Replacement Therapy for Spinal Muscular Atrophy: Clinical Development
SMN 替代疗法治疗脊髓性肌萎缩症:临床开发
  • 批准号:
    G1001492/1
  • 财政年份:
    2012
  • 资助金额:
    $ 54.98万
  • 项目类别:
    Research Grant

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  • 批准号:
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    70.0 万元
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