Investigating Stakeholder Perspectives to Inform Ethical Use of Organoids in Pediatric Rare Disease Research

总结 类器官是通过将干细胞编程为器官特异性细胞而产生的体外三维结构 类型这些细胞以模仿完整器官的结构和功能的方式自我组织，这使得 类器官作为健康和疾病系统中器官的细胞模型。从患者生成时 干细胞，它们含有患者的DNA，可以重现器官特异性疾病表型。类器官 因此可以用于实验，如基因改造和个性化治疗试验， 而不使病人遭受身体和医疗风险。母公司奖，系统识别和 罕见疾病相关出生缺陷中因果遗传变异的表型表征， 来自儿科患者的异常脑形态的患者来源的脑类器官模型。这些脑 类器官通过单细胞和空间转录组学进行功能分析， 经修饰以在功能上表征候选致病遗传变体。这些类器官研究 在识别致病遗传变异和表征其功能后果方面的前景。然而，在这方面， 由于类器官来源于患者组织，因此它们不被视为道德中立， 由于大脑在自我和人性概念中的核心作用，被认为具有特殊的道德价值。而 类器官在生物医学研究中的应用正在迅速发展，类器官使用的生物伦理学研究正在进行。 它的婴儿期。因此，类器官的道德和法律的地位还有待于政策和法规的界定。 具体到类器官用途还有待开发。本附录旨在提供证据基础， 通过探索对类器官及其功能的认识，为研究中使用类器官的政策提出建议。 在关键利益相关者中用于儿科罕见病研究。本研究将对1） 确诊或疑似罕见疾病的青少年和年轻成人患者，2）患有 诊断或疑似罕见疾病，3）积极研究类器官的研究人员，4）生物伦理学家， 儿科学、研究伦理学和/或新兴技术方面的专业知识。病人和家长的谈话将 探索对类器官的感知以及与来自患者的各种类器官类型的想象联系 组织中他们还将探讨患者和家长对研究中使用类器官的希望和担忧 以及所需的限制和保护。这些数据将被纳入研究人员的采访指南， 生物伦理学家不仅会被要求他们自己认为的类器官研究的好处和风险， 考虑患者和家长访谈的结果，提出潜在的解决方案， 用于类器官研究并提供必要的保护。分析将被报告并用于生成 围绕类器官在研究中的使用提出基于证据的政策建议。

SUMMARY Organoids are three-dimensional in vitro structures generated by programming stem cells into organ specific cell types. These cells self-organize in ways that mimic the structure and function of intact organs, which allows organoids to act as cellular models for organs in healthy and disease systems. When generated from patient stem cells, they contain the patient’s DNA and can recapitulate organ-specific disease phenotypes. Organoids can therefore be used for experimentation such as genetic modification and personalized therapeutic trials without subjecting patients to physical and medical risks. The parent award, Systematic Identification and Phenotypic Characterization of Causal Genetic Variants in Rare Disease-Associated Birth Defects, generates patient-derived brain organoid models of abnormal brain morphology from pediatric patients. These brain organoids are functionally profiled through single-cell and spatial transcriptomics and may be genetically modified to functionally characterize candidate causal genetic variants. These organoid studies hold great promise in identifying causal genetic variants and in characterizing their functional consequences. However, because organoids are derived from patient tissues they are not seen as morally neutral, with brain organoids perceived as having special moral value due to the brain’s central role in the concept of self and humanity. While the use of organoids in biomedical research is advancing quickly, the study of the bioethics of organoid use is in its infancy. Therefore, the moral and legal status of organoids has yet to be defined and policies and regulations specific to organoid use have yet to be developed. This supplement aims to provide an evidence-base and recommendations for policy around organoid use in research by exploring perceptions of organoids and their use in pediatric rare disease research in key stakeholders. The study will conduct in-depth interviews with 1) adolescent and young adult patients with diagnosed or suspected rare conditions, 2) parents of child with diagnosed or suspected rare conditions, 3) researchers actively working with organoids, and 4) bioethicists with expertise in pediatrics, research ethics, and/or emerging technologies. The patient and parent interviews will explore perceptions of organoids and imagined connection with various organoid types derived from patient tissues. They will also explore patient and parent perceived hopes and concerns for organoid use in research and desired limitations and protections. This data will be integrated into interview guides for researchers and bioethicists who will be asked not only their own perceived benefits and risks of organoid research, but to consider the findings from patient and parent interviews to suggest potential solutions that both preserve potential for organoid research and provide needed protections. The analysis will be reported and used to generate evidence-based recommendations for policies around organoid use in research.