Providing ethical guidance for the development of individualized genomic medicine as rare as n-of-1

为罕见的个体化基因组医学的开发提供伦理指导

• 批准号: 10528696
• 负责人: Lynn Bush
• 金额: $ 73.84万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10528696
• 关键词: Address; American; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Authorization documentation; Bioethics Consultants; Catalogs; Child; Complex; Consensus; Consent; Custom; Development; Disease; Disease Progression; Eligibility Determination; Ethics; Family; Foundations; Future; Gene Targeting; Genetic Diseases; Genomic medicine; Goals; Health; Incentives; Individual; Informed Consent; Institution; Institutional Review Boards; Intervention; Interview; Investigational Therapies; Investments; Journals; Justice; Malignant Neoplasms; Medicine; Methods; Morbidity - disease rate; Neurodegenerative Disorders; Neurologist; Nurses; Outcome; Parents; Pathogenicity; Patient advocacy; Patients; Peer Review; Pharmaceutical Preparations; Policies; Process; Rare Diseases; Recommendation; Reporting; Research Personnel; Resources; Safety; Science; Scientist; Seizures; Sickle Cell Anemia; Site; Source; Spielmeyer-Vogt Disease; Surveys; Technology; Testing; Therapeutic; Time; United States Food and Drug Administration; Work; base; case-based; cost; design; editorial; ethical legal social implication; experience; genetic variant; genome editing; girls; individualized medicine; innovation; interest; meetings; mortality; multidisciplinary; new technology; novel; optimism; social; sociologist; symposium; targeted treatment; therapeutic development; therapeutic misconception; underserved community

PROJECT SUMMARY Many Americans (mostly children) have a genetic disease so rare it is termed an “orphan disease” with no approved treatment and little incentive for investment in therapy given the rarity. However, it is now possible to design, develop, and deliver gene-targeted treatments that work for as few as a single patient, i.e., as truly individualized medicines. These “n-of-1” treatments began with a class of drugs called “antisense oligonucleotides” (ASOs), first demonstrated in 2018 when a customized ASO was designed to target a specific pathogenic genetic variant on behalf of a child with a fatal and otherwise untreatable genetic condition. This effort created a blueprint for treating other individuals with orphan diseases. Not surprisingly, that pilot case brought forth a multitude of hopeful families asking about their children’s eligibility for similar interventions, and at least six academic institutions have launched efforts in this space to develop additional individualized n-of-1 therapies. The development of customized investigational therapies for single or few individuals is at present expensive, both in terms of cost and time, and raises a host of ethical, legal, and social implication (ELSI) challenges, including justice, equity, therapeutic misconception, hope-therapeutic optimism, informed consent, experimental treatment of children unable to consent or assent, best interests of the child, and appropriate thresholds of evidence for safety and efficacy when dealing with fatal orphan diseases that lack other treatments. There is a critical need to gather input from diverse stakeholders to address these considerations and provide guidance, not only for sake of those interested in individualized ASO development, but for other emerging gene-targeting therapeutic platforms that might be similarly individualized (e.g., genome editing). The goal of this study is to develop and deliver empirically-informed guidance that addresses the complex ELSI of individualized genomic medicine, and to chart a course that is just, fair, equitable, transparent, and socially responsible. In Aim 1 we will conduct qualitative interviews with a diverse set of stakeholders: ASO Site teams involved in the development of individualized therapies, Societal Issue experts (including leaders of underserved communities), Parents of children with and without genetic conditions, Oversight experts without n-of-1 ASO experience, and representatives of foundations and patient advocacy. In Aim 2, informed by our experience and combined with domains and themes identified in Aim 1, we will combine a case-based modified Delphi process, capped by a roundtable session to develop two tiered guidance for addressing the ELSI challenges attendant to individualized therapy: 1) recommendations (“overall consensus”) and 2) points to consider (key issues below the pre-determined threshold of “overall consensus”), along with a source casebook. The two tiered guidance will inform evolving policies around the provision of individualized genomic medicine for orphan diseases. Findings and recommendations will be broadly disseminated in a half-day conference, as well as global professional meetings and in peer-reviewed journals.

项目概要 许多美国人（主要是儿童）患有一种非常罕见的遗传病，被称为“孤儿病”，没有任何疾病可以治愈。 批准的治疗方法，并且鉴于其稀有性，几乎没有动力投资于治疗。 设计、开发和提供针对单个患者的基因靶向治疗，即真正有效的治疗 这些“n-of-1”治疗始于一类称为“反义药物”的药物。 寡核苷酸”（ASO），于 2018 年首次展示，当时设计了定制的 ASO 来靶向 代表患有致命且无法治疗的遗传病的儿童的特定致病遗传变异。 这项努力为治疗其他患有孤儿疾病的人创造了蓝图，这一点并不奇怪。 该案件引起了众多充满希望的家庭询问他们的孩子是否有资格获得类似的 干预措施，并且至少有六个学术机构已在这一领域开展了努力，以开发更多 个体化的 n-of-1 疗法。针对单个或少数几个的定制研究疗法的开发。 目前，个人的成本和时间都很昂贵，并引发了一系列道德、法律和社会问题 暗示（ELSI）挑战，包括正义、公平、治疗误解、希望治疗乐观主义、 知情同意、对无法同意或不同意的儿童进行实验性治疗、儿童的最大利益、 以及处理致命孤儿疾病时安全性和有效性的适当证据阈值 缺乏其他治疗方法，迫切需要收集不同利益相关者的意见来解决这些问题。 考虑并提供指导，不仅是为了那些对个性化 ASO 开发感兴趣的人， 但对于其他可能同样个性化的新兴基因靶向治疗平台（例如基因组 本研究的目标是制定并提供基于经验的指导，以解决以下问题： 个体化基因组医学复杂的ELSI，并制定公正、公平、公正、透明的路线， 在目标 1 中，我们将与不同的利益相关者进行定性访谈：ASO。 参与个体化疗法开发的现场团队、社会问题专家（包括 服务不足的社区）、有或没有遗传疾病的儿童的父母、没有遗传病的监督专家 n-of-1 ASO 经验，以及基金会代表和患者倡导 In Aim 2，由我们告知。 经验并结合目标 1 中确定的领域和主题，我们将结合基于案例的 修改后的德尔菲流程，以圆桌会议为结束，以制定两层指南来解决 个体化治疗面临的 ELSI 挑战：1) 建议（“总体共识”）和 2) 要点 考虑（低于“总体共识”预定阈值的关键问题），以及来源 两层指南将为围绕提供个性化基因组的不断发展的政策提供信息。 研究结果和建议将在半天内广泛传播。 会议、全球专业会议和同行评审期刊。