Planar culture of gastrointestinal stem cells for screening pharmaceuticals for adverse event risk

胃肠道干细胞平面培养用于筛选药物不良事件风险

基本信息

  • 批准号:
    10707830
  • 负责人:
  • 金额:
    $ 91.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary GI side effects, such as ulcers and diarrhea, represent the most common source of adverse events for pharmaceuticals. GI stem cells are responsible for repairing and replenishing GI epithelium, and pharmaceutical inhibition of these functions likely contribute to adverse event risk. Currently there are no high-throughput and cost-effective means of screening candidate therapeutics for effects on GI stem cells. Animal models are fraught with confounds (e.g., rats generally do not exhibit diarrhea until death is imminent) and current in vitro models like the Caco-2 tumor cell line do not include a normal stem cell population. While 3D-organoid cultures have a stem cell component, access to the apical aspect of the monolayer for compound exposure is not possible without low-throughput microinjection. Altis Biosystems, Inc. has developed a proprietary culture platform, RepliGut® Planar, enabling primary human GI cells to form an epithelium for drug screening. In preliminary efforts, we initiated development of a GI stem cell-specific platform called RepliGut® StemScreen to address the unmet need for high-throughput, cost-effective GI stem cell screening, including a range of assays to measure properties that might lead to adverse events. These included assays related to stem cell proliferation, self- renewal, and differentiation competency. In our Phase 1 studies, we developed a 5 day, 96-well, plate-based screening assay (termed StemTox) and tested a panel of pharmaceutical agents known to trigger GI side effects. The results revealed a highly sensitive and dose-dependent inhibition of stem cell proliferation and impairment of intestinal barrier formation. Furthermore, our assay detected “adverse” concentrations for compounds that closely paralleled the clinical plasma Cmax associated with human clinical outcomes. In this Phase 2 application, we propose to complete optimization of the StemTox screen, generate a commercial validation data set (using multiple tissue donors and cell lots of transverse colon), and expand the model to integrate cell differentiation and long-term drug exposures. Collectively, this work will result in the commercial launch of the StemTox assay, as well as, enable several follow-on experimental paradigms to more comprehensively assess off-target drug mechanisms and repeat- dosing experiments (to parallel current IND-enabling nonclinical study requirements).
项目总结

项目成果

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Bill Thelin其他文献

Bill Thelin的其他文献

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{{ truncateString('Bill Thelin', 18)}}的其他基金

MetabolGut: a rapid assay platform to evaluate the impact drugs on lipid-handlingpathways and chylomicron-associated drug distribution using stem cell-drivenhuman absorptive enterocytes.
MetabolGut:一个快速检测平台,使用干细胞驱动的人体吸收性肠上皮细胞来评估药物对脂质处理途径和乳糜微粒相关药物分布的影响。
  • 批准号:
    10766493
  • 财政年份:
    2023
  • 资助金额:
    $ 91.37万
  • 项目类别:

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