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

项目总结 许多美国人(主要是儿童)患有一种罕见的遗传病，被称为“孤儿病”，没有 考虑到这种罕见的情况，批准的治疗和对治疗的投资几乎没有激励。然而，现在有可能 设计、开发和提供对单个患者有效的基因靶向治疗，即真正 个体化药物。这些“n-of-1”疗法始于一种名为“反义”的药物。 寡核苷酸“(ASOS)，于2018年首次演示，当时定制的ASO旨在针对 代表患有致命或其他无法治疗的遗传病的儿童的特定致病基因变异。 这一努力为治疗其他患有孤儿疾病的人创造了一幅蓝图。毫不奇怪，那个飞行员 此案带来了许多充满希望的家庭，询问他们的孩子是否有资格获得类似的 干预措施，至少有六个学术机构在这一领域发起了努力，以开发更多 个体化n-of-1疗法。单项或少数患者个体化研究疗法的发展 个人目前在成本和时间方面都很昂贵，并引发了许多道德、法律和社会问题 影响(ELSI)挑战，包括正义、公平、治疗误解、希望-治疗乐观、 知情同意，对不能同意或同意的儿童的试验性治疗，儿童的最大利益， 在处理致命的孤儿疾病时，安全性和有效性的证据的适当阈值 缺乏其他治疗方法。迫切需要从不同的利益相关者那里收集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， 但对于其他可能类似个性化的新兴基因靶向治疗平台(例如，基因组 编辑)。这项研究的目标是开发和提供经验性的指导，以解决 个体化基因组医学的复杂ELSI，并绘制出一条公正、公平、公平、透明、 和社会责任感。在目标1中，我们将对不同的利益相关者进行定性访谈：麻生 参与个性化治疗开发的现场团队、社会问题专家(包括 服务不足的社区)，患有和不患有遗传病的儿童的父母，没有 N-of-1 ASO经验，以及基金会和患者倡导的代表。在Aim 2中，由我们的 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 修改的德尔福流程，由圆桌会议结束，以制定两级指导，以解决 ELSI对个体化治疗的挑战：1)建议(“总体共识”)和2)要点 审议(低于预先确定的“总体共识”门槛的关键问题)，并提供资料来源 案例簿。这两个层次的指导将为围绕提供个性化基因组的不断发展的政策提供信息 治疗孤儿疾病的药物。调查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议的期刊。

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.