Toward an Extensible Regulatory Framework for N-of-1 to N-of-Few Personalized RNA Therapy Design.

Abstract

The emergence of personalized RNA therapeutics, tailored to individual patients' genetic profiles, offers new hope for treating both common and rare diseases. This review explores regulatory aspects of N-of-1 and N-of-few approaches, providing promising treatments for ultra- or nano-rare diseases that lack established therapies. These diseases present unique challenges, as patients may represent the sole individual or a small group worldwide with a specific mutation, necessitating personalized approaches to treatment development, validation, and approval. While progress is promising, the regulatory landscape remains nascent, raising challenges in ensuring safety and industry sustainability. Artificial intelligence (AI) and automated systems, coupled with real-world evidence (RWE) monitoring, offer significant potential to address these challenges by optimizing development, manufacturing, and regulatory compliance. Drawing parallels from other regulatory domains, this review presents a design envelope framework, integrated with AI tools, to streamline the approval process and enhance the adaptability of RNA-based treatments. Case studies of individualized RNA-based treatments highlight successes and setbacks, underscoring the need for regulatory alignment. Collaborative efforts from stakeholders and regulatory authorities are essential to refine this framework for real-world application. Overall, this review emphasizes the transformative potential of personalized RNA therapeutics in advancing precision medicine.