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

调查利益相关者的观点，为儿科罕见病研究中类器官的道德使用提供信息

• 批准号: 10791976
• 负责人: Scott T Younger
• 金额: $ 24.51万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10791976
• 关键词: 3-Dimensional; Accountability; Adolescent and Young Adult; Animal Model; Animals; Architecture; Attention; Attitude; Award; Benefits and Risks; Bioethics; Bioethics Consultants; Biological; Biological Models; Biomedical Research; Brain; Cell Line; Cell model; Cells; Child; Childhood; Clustered Regularly Interspaced Short Palindromic Repeats; Congenital Abnormality; DNA; Data; Dependence; Development; Diagnosis; Diagnostic; Disease; Disease model; Embryo; Emerging Technologies; Empirical Research; Ethics; Etiology; Experimental Genetics; Family; Feeling; Genetic; Genetic Diseases; Heart; Human; Humanities; In Vitro; Individual; Informed Consent; Interview; Kidney; Knowledge; Legal Status; Liver; Medical; Modeling; Modification; Morals; Natural regeneration; Organ; Organ Model; Organoids; Parents; Participant; Patients; Pediatrics; Perception; Phenotype; Physiology; Policies; Process; Published Comment; Rare Diseases; Regulation; Reporting; Research; Research Ethics; Research Personnel; Risk; Role; Sampling; Structure; System; Technology; Testing; Therapeutic Agents; Therapeutic Trials; Tissues; Trust; Vulnerable Populations; biobank; brain abnormalities; brain morphology; cell type; clinical diagnosis; development policy; disease phenotype; evidence base; evidence based guidelines; experience; gene therapy; genetic variant; genome editing; human DNA; human stem cells; human tissue; infancy; pediatric patients; personalized therapeutic; policy recommendation; preservation; rare condition; self organization; stakeholder perspectives; stem cell differentiation; stem cells; transcriptomics

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.

概括 类器官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 这些细胞以模仿完整器官的结构和功能的方式进行自组织，从而允许 从患者身上产生的类器官可作为健康和疾病系统中器官的细胞模型。 干细胞，它们含有患者的 DNA，可以概括器官特异性疾病表型。 因此可用于基因改造和个性化治疗试验等实验 不会让患者面临身体和医疗风险 家长奖励、系统识别和 罕见病相关出生缺陷的因果遗传变异的表型特征，生成 来自儿科患者的异常大脑形态的患者衍生脑类器官模型。 通过单细胞和空间转录组学对类器官进行功能分析，并且可能是遗传性的 进行修改以在功能上表征候选因果遗传变异。这些类器官研究具有重要意义。 有望识别因果遗传变异并描述其功能后果。 因为类器官来自患者组织，所以它们不被视为道德中立，而大脑类器官 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。 类器官在生物医学研究中的应用正在迅速推进，类器官使用的生物伦理学研究正在进行中 因此，类器官的道德和法律地位尚未确定，政策和法规也尚未确定。 针对类器官的使用尚未开发，该补充旨在提供证据基础和 通过探索对类器官及其作用的看法，就类器官在研究中的使用提出政策建议 该研究将对主要利益相关者进行深入访谈 1) 患有诊断或疑似罕见疾病的青少年和年轻成人患者，2) 患有以下疾病的儿童的父母 已诊断或疑似罕见病症，3）积极研究类器官的研究人员，以及 4）生物伦理学家 患者和家长的访谈将涉及儿科、研究伦理和/或新兴技术方面的专业知识。 探索对类器官的看法以及与来自患者的各种类器官类型的想象联系 他们还将探讨患者和家长对类器官在研究中使用的期望和担忧。 以及所需的限制和保护。这些数据将被纳入研究人员和人员的访谈指南中。 生物伦理学家不仅会被问到他们自己认为的类器官研究的好处和风险，而且还会被问及 考虑患者和家长访谈的结果，提出既保留潜力又可能的解决方案 用于类器官研究并提供所需的保护 分析结果将被报告并用于生成。 针对研究中类器官使用的政策提出基于证据的建议。