How can rare disease innovation move faster without lowering scientific or regulatory standards? In this interview, PJ Brooks explains how the National Center for Advancing Translational Sciences is shifting rare disease development toward platform-based thinking, shared molecular pathways, and early regulatory alignment. From genome editing and gene therapy to open data and newborn screening, the discussion highlights how system-level change may unlock progress for even the rarest conditions.
What is the role of the Division of Rare Diseases Research Innovation within NCATS, and how does it advance translation in rare diseases?
The Division of Rare Diseases Research Innovation sits within the National Center for Advancing Translational Sciences, one of the institutes of the US National Institutes of Health. NCATS has a distinct mandate within NIH. Rather than focusing on specific diseases, we focus on the translational process itself and on how to make that process faster, more efficient, and more reliable. The objective is to bring more treatments to more people, more quickly. Within that framework, our division concentrates on rare diseases, which present particular challenges related to small patient populations, limited commercial incentives, and the complexity of clinical trial design.
A central part of our approach is to move beyond a purely phenotype-based definition of disease. Instead of defining conditions only by their signs and symptoms, we increasingly focus on shared molecular abnormalities. When multiple rare diseases are driven by the same underlying pathway, it becomes possible to develop therapies and design clinical trials that cut across traditional disease boundaries. This pathway-based strategy, long established in oncology, allows patients with different rare conditions to be enrolled in the same trial when the intervention targets a common molecular mechanism. We have several programs built around this model, including small-molecule efforts that have already secured Investigational New Drug approvals and are progressing toward clinical evaluation.
From a translational standpoint, one of our most important long-standing initiatives is the Rare Diseases Clinical Research Network. This is a National Institutes of Health-wide program led by NCATS that supports multi-site clinical research, natural history studies, and trial readiness across hundreds of rare diseases. A significant emphasis is placed on generating the foundational data required for clinical trials, including well-characterized natural histories and meaningful clinical endpoints. Although this work is often undervalued, it is essential for successful translation. The network operates in defined funding phases, and in the current phase each project must include at least three rare diseases, reflecting our focus on efficiency, shared learning, and improved patient access.
In parallel, we support innovative clinical trial designs and require early engagement with the FDA so investigators can receive regulatory feedback as part of the development process. Beyond therapeutic development, we also support the Genetic and Rare Diseases Information Center, a congressionally mandated program within NCATS that provides free, evidence-based information to patients, families, and healthcare professionals. Together, these efforts reflect a broad and integrated approach to translation, spanning trial readiness, regulatory alignment, and access to trusted information, all with the aim of improving outcomes for people living with rare diseases.
How are platform-based approaches reshaping rare disease development, and what has your experience shown about regulatory engagement and readiness for these models?
Platform-based approaches are increasingly central to how we think about rare disease development, particularly as the field moves beyond the traditional one-therapy, one-disease model. One of the most important examples is the Somatic Cell Genome Editing program, which NCATS co-leads with the National Institute of Neurological Disorders and Stroke and which is funded through the NIH Common Fund. These programs are designed to address challenges that cut across the NIH, and we are now in the second phase, with a clear emphasis on moving genome-editing technologies toward clinical application.
A defining feature of this phase is the requirement to demonstrate a true platform strategy. Investigators are expected to work with a single genome editor and delivery system across multiple diseases, while engaging early and formally with the FDA to explore how such approaches can be evaluated efficiently. An equally important element is the commitment to sharing regulatory insights openly, allowing the broader research community to learn from these interactions in ways that are difficult for private industry to do because of intellectual property constraints.
One of the most visible outcomes of this effort involved a personalized gene-editing therapy for an infant with a severe urea cycle disorder, often referred to as Baby KJ. Supported through an SCGE-funded project led by Dr Rebecca Ahrens-Nicklas and Dr Kiran Musunuru, the team moved from a precise molecular diagnosis to a first-in-human treatment in approximately six to seven months. While the case attracted significant attention, it was never intended as an end-of-one solution. The project was designed around urea cycle disorders as a group, using shared molecular mechanisms to demonstrate gene editing as a reusable therapeutic platform rather than a bespoke intervention for a single patient.
What made this possible was the groundwork laid well in advance. The investigators had already spent substantial time generating preclinical data and engaging with the FDA, including pre-IND discussions around an umbrella trial design that could enroll patients with multiple related disorders under a single protocol, with only the guide sequence varying between conditions. The FDA responded positively to this approach, and the subsequent publication in The American Journal of Human Genetics documented both the regulatory dialogue and its broader implications. Taken together, these experiences have been encouraging, showing that regulators are ready to engage thoughtfully with platform-based technologies and that early, transparent collaboration is essential if these approaches are to scale beyond isolated successes and deliver broader impact for rare disease patients.
What was the rationale behind establishing the Bespoke Gene Therapy Consortium, and what has it revealed about the practical limits and opportunities of platform-based gene therapy?
The Bespoke Gene Therapy Consortium was established in 2021 to address a recurring gap in rare disease development, namely the number of scientifically credible gene therapy programs that struggle to move forward because the diseases are too rare to support a conventional commercial model. Organized through the Foundation for the National Institutes of Health, the consortium brings together the National Institutes of Health, the FDA, industry partners, nonprofit organizations, and patient groups, creating a structure that allows public and private stakeholders to work together in a pre-competitive setting.
The focus of the consortium is on improving efficiency and predictability across the development pathway, from preclinical proof of concept to first-in-human trials. We began with seven ultra-rare diseases, pooling funding from multiple partners and several NIH institutes, with the intention of advancing each program while systematically capturing and sharing lessons learned. A major emphasis has been on standardization, particularly around defining a minimal and consistent set of critical quality attributes for adeno-associated virus vectors, as well as identifying a streamlined package of animal toxicology studies that could support early clinical development. These are areas where practices have historically varied widely, often adding time and cost without necessarily improving outcomes.
One of the most tangible outputs of this work is the BGTC Playbook, a publicly available resource that lays out the full AAV gene therapy development process from animal studies through to first-in-human trials. The playbook is designed to evolve as new insights emerge and as streamlining efforts mature, providing a practical reference for groups working on diseases that fall well outside traditional commercial interest. At the same time, the consortium has reinforced an important reality, which is that AAV-based gene therapy is not a simple plug-and-play platform. Each program brings its own manufacturing, consistency, and safety challenges, making the process more complex and less predictable than originally assumed.
This experience has helped clarify why gene editing may offer greater long-term platform potential. Gene-editing systems are inherently modular, built around a stable editor and delivery system, with only the guide RNA changing between targets. Engagements with the FDA have confirmed that this modularity can translate into regulatory flexibility, including reduced requirements for repeat animal studies when core components remain unchanged. Taken together, the work of the consortium is helping to define how regulators and developers can think about gene editing as a reusable therapeutic approach rather than a sequence of one-off products, with meaningful implications for how ultra-rare diseases might be addressed in the future.
Looking ahead, what do you see as the main barriers to scaling platform-based therapies across rare diseases, particularly beyond scientific and regulatory considerations?
Looking ahead, one of the most significant barriers is not the science or the regulatory framework, but the lack of business models that align with platform-based therapies. These technologies are designed to be applied across multiple diseases, yet commercial development is still largely organized around individual indications, where pricing and return on investment can be calculated based on patient numbers. That approach is understandable, but it does not sit comfortably with the idea of a reusable therapeutic platform intended to serve many ultra-rare conditions.
The open question is whether viable models can be built around the platform itself rather than around a single disease. This is not something we are positioned to solve, and it is not my area of expertise, but it is becoming increasingly central as these technologies mature. Without progress on this front, there is a real risk that gene editing and similar approaches will continue to be applied one disease at a time, with development naturally focusing on the more common genetic disorders. From a scientific standpoint, however, many ultra-rare diseases are monogenic, and the underlying problem, and therefore the solution, is often fundamentally the same regardless of disease prevalence.
This is why alternative approaches to commercialization are beginning to matter more. We are already seeing examples in which non-traditional, non-profit organizations step in where conventional commercial pathways fall short. A notable case is the San Raffaele Telethon Institute for Gene Therapy in Italy, which successfully brought an ex vivo gene therapy for Wiskott–Aldrich syndrome into clinical use after industry partners withdrew. That experience suggests there may be viable pathways beyond traditional for-profit models, and I expect this area will attract increasing attention in the coming years as the field looks for ways to ensure that platform-based technologies reach patients with the rarest diseases.
What other initiatives illustrate how NCATS is addressing persistent gaps in rare disease development and diagnosis?
One area that has attracted considerable attention is the use of antisense oligonucleotides, particularly for ultra-rare, monogenic conditions. A widely cited early example came from work led by Dr Timothy Yu at Boston Children’s Hospital, where a customized antisense therapy was developed for a child with a rare form of Batten disease. In that case, the team moved from a precise molecular diagnosis to administering a first treatment in just over a year, demonstrating how rapidly these technologies can be adapted and highlighting their potential as a therapeutic platform for certain classes of rare disease.
Experience has also shown that antisense approaches are less straightforward than they may initially appear. Toxicity is difficult to predict even when chemical backbones are held constant, as small sequence changes can result in markedly different safety profiles. As a result, animal toxicology studies are still often required. One area we are now exploring is whether advances in artificial intelligence could help address this limitation. We have recently launched a prize competition to identify high-quality human data sets that could be used to train predictive models of oligonucleotide toxicity, with a strong emphasis on placing those data in the public domain so they can be broadly reused and refined by the community.
Open data more broadly is a central priority for NCATS. During the COVID-19 pandemic, colleagues in the Division of Preclinical Innovation developed public databases that made information on drugs, antibodies, and other interventions widely accessible. In rare diseases, where patient numbers are limited and resources are constrained, this kind of openness is particularly important to reduce duplication and accelerate progress. We also remain very conscious of the role families often play in driving early research, and of the need to lower the barriers that force parents to become de facto developers.
Finally, we are applying platform thinking to diagnosis as well as therapy. A recent initiative, Newborn Screening by Whole Genome Sequencing (NBSxWGS), is a pilot program designed to assess whether whole genome sequencing could be integrated into existing newborn screening systems in the United States. The focus is not on immediate implementation, but on understanding the technical, operational, and system-level challenges, including how sequencing might be incorporated into state public health laboratories without overwhelming current workflows. The aim is to learn what would be required to make such an approach viable in the future, with the longer-term goal of shortening diagnostic journeys and easing the burden on families affected by rare genetic diseases.
