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

项目总结

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.