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

摘要 类有机物是通过将干细胞编程为器官特异性细胞而产生的三维体外结构 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 有机化合物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，它们包含患者的DNA，可以概括特定器官的疾病表型。有机类化合物 因此可以用于实验，如基因改造和个性化治疗试验 而不会让患者面临身体和医疗风险。家长奖、系统鉴定和 罕见疾病相关出生缺陷的因果遗传变异的表型特征 儿科患者异常脑形态的患者衍生脑器官模型。这些大脑 有机化合物通过单细胞和空间转录组学在功能上进行分析，并可能是遗传上的 对其进行修改以从功能上表征候选的因果遗传变异。这些有机化合物研究很有说服力 在识别因果遗传变异和描述其功能后果方面的承诺。然而， 因为有机化合物是从病人的组织中提取出来的，所以它们在道德上并不被视为中性，与脑有机化合物一样 由于大脑在自我和人性概念中的中心作用，被认为具有特殊的道德价值。而当 有机化合物在生物医学研究中的应用进展迅速，有机化合物使用的生物伦理学研究正在进行中 它还处于初级阶段。因此，有机化合物的道德和法律地位尚未确定，政策和法规尚未确定。 具体到有机化合物的使用还有待开发。本补充文件旨在提供一个证据基础和 通过探索人们对有机化合物及其化合物的认识，为研究中有机化合物的使用提供政策建议 在关键利益攸关方的儿科罕见疾病研究中使用。该研究将对1)进行深入访谈 确诊或疑似罕见疾病的青少年和青壮年患者，2)儿童的父母 诊断或怀疑罕见疾病，3)研究人员积极研究有机物质，4)生物伦理学家 儿科学、研究伦理和/或新兴技术方面的专业知识。患者和家长的面谈将 探索患者对有机物质的认知及其与各种有机物质类型的想象联系 纸巾。他们还将探索患者和家长对有机化合物在研究中使用的期望和担忧 以及所需的限制和保护。这些数据将整合到研究人员的采访指南中，并 生物伦理学家不仅会被问到他们自己对有机化合物研究的感知到的好处和风险，而且还会被问到 考虑患者和家长访谈的结果，建议既保留潜力又有潜力的潜在解决方案 用于有机物研究，并提供必要的保护。分析将被报告并用于生成 关于有机化合物在研究中使用的政策的循证建议。

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.