The N=1 Collaborative: advancing customized nucleic acid therapies through collaboration and data sharing

Jillian Belgrad, Erin McConnell, Stef Leonard, Nicole Nolen, Marlen C Lauffer, Jonathan K Watts, Timothy Yu, Winston X Yan, Annemieke Aartsma-Rus

April 25, 2025

Abstract

Developing customized gene-targeting therapies for the millions of individuals affected by ultra-rare diseases globally requires breaking new ground in therapeutic and regulatory innovation. To address this need, the N=1 Collaborative (N1C) was established to unite academia, industry, patients, and regulators, building an open, shared ecosystem for personalized medicines. Initially focusing on antisense oligonucleotides (ASOs) for rare, fatal neurodegenerative conditions, the N1C aims to develop frameworks that can rapidly extend to other treatment modalities and conditions. Progress in the advancement of personalized therapies has also propelled advancements in the nucleic acids field, offering critical insights into dosing, safety, and efficacy. In October 2024, the N1C convened scientific, regulatory, and advocacy leaders in ASO development for an inaugural meeting. This review report examines the current state of the scientific and clinical ecosystems enabling customized genetic therapies and explores the innovation, frameworks, and systems needed to deliver additional individualized medicines safely and at scale.

Introduction

For patients with ultra-rare diseases, the path to treatment is often uncharted. One poignant example is that of Mila Makovec, diagnosed with Batten disease caused by pathogenic variants in CLN7 (MFSD8) in 2017 [1]. CLN7 Batten disease is a late-infantile onset, progressive neurodegenerative disease, leading to vision loss, seizures, dementia, motor dysfunction, and premature death. Due to the condition’s rarity and intronic location of her mutation, Mila had a protracted diagnostic odyssey, eventually requiring whole genome sequencing to identify a critical pathogenic deep intronic variant in CLN7, resulting in activation of a cryptic splice site that truncated the gene. While no traditional treatment options were available to modify the CLN7 Batten disease course, cryptic splicing variants are ideal targets for splice-modulating antisense oligonucleotides (ASOs). At the time of discovering the cryptic splicing variant, another splice-switching ASO, nusinersen, had just been approved by the Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy [2]. Nusinersen is delivered intrathecally and achieves widespread uptake throughout the central nervous system, demonstrating the feasibility of ASO treatment of brain and spinal cord diseases. Building on this breakthrough, a customized ASO therapy—later named milasen—was developed specifically for Mila by Dr Tim Yu at Boston’s Children Hospital within a remarkably short time: the experimental therapy was initiated within 10 months of completing the genetic diagnosis [1]. Milasen not only improved Mila’s symptoms but also demonstrated that individualized therapy development is possible. This groundbreaking case inspired broader efforts to bring personalized therapies to others with serious, life-limiting, rare genetic diseases.

Several organizations—including the Dutch Center for RNA therapeutics, the n-Lorem Foundation, and various academic medical centers—began developing similar individualized therapy programs [3, 4]. Pharmaceutical companies like EveryOne Medicines also expressed interest, seeing the potential of individualized therapies to address previously unmet medical needs.

The need for a collaborative effort

While each n-of-1 ASO has to be developed for a unique context, requiring specific ASO design and preclinical testing, many processes of ASO development are shared [5]. Furthermore, one can build on prior lessons learned from individual ASO developments that were successful or not. Thus, open sharing of data and experiences across n-of-1 programs provides a powerful mechanism to accelerate progress, particularly for platform modalities like ASOs. These platforms would create unique opportunities to connect clinical outcomes with sequence- or chemistry-specific toxicity data, informing trends in future drug development. Beyond advancing the science, transparent knowledge sharing fulfills an ethical imperative. Individuals with ultra-rare diseases often face limited or no treatment options, so ensuring that lessons learned from one case can inform others is essential to maximizing the impact of each therapeutic effort.

To address this critical need, the N=1 Collaborative (N1C)—a global platform for knowledge and data sharing—has taken the lead in fostering cross-sector dialogue, bringing together experts from academia, industry, regulatory agencies, and patient communities to drive progress in individualized therapies. Founded as a 501(c)(3) non-profit organization, N1C serves as an independent and neutral platform dedicated to advancing individualized medicines. Rather than directly developing n-of-1 treatments, N1C facilitates progress by providing guidance, frameworks, and shared infrastructure to empower stakeholders. By catalyzing the creation and dissemination of a rigorous, reproducible, and openly available pathway, N1C ensures that researchers, clinicians, drug developers, and patient communities can work together effectively. N1C enables data sharing through its efforts to create open databases of cases of mutations amenable to ASO correction, shared oligonucleotide controls for screening standardization, and regulatory document samples to hasten the formation of data packages for smaller clinical teams. Furthermore, it commits to continuously refining these resources to shape future best practices, driving the field toward sustainable growth and broader accessibility.

This N1C community is organized into working groups that focus on specific aspects of n-of-1 treatment development. N1C working groups have provided updates and learnings through online webinars and publications (https://www.n1collaborative.org/resources). Current N1C working groups include but are not limited to patient identification, preclinical development, data coordination, chemistry, manufacturing and control, institutional implementation, clinical outcomes, and access. The N1C working groups are linked by a Scientific Advisory Board, comprised of experts aligning in each of the key working group areas. In parallel to the scientific and clinical endeavors of N1C, the organization is propelled by its operation team and board of directors to support and make N1C efforts possible. N1C does not directly build therapeutics itself. Instead, the work of N1C aims to serve as collaborative enabler, paving paths for others to develop and dose customized nucleic acid-based therapeutics for patients with orphan diseases safely, rapidly, and at a global scale. N1C held its inaugural meeting in October 2024, showcasing recent collaborative development and brought together members, key stakeholders, and interested parties to plan for the future (https://www.n1collaborative.org/annual-meeting). This review provides context to the concept of individualized treatment development, its challenges and highlights insights from the 2024 Annual Meeting, and examines the scientific and regulatory advancements needed to expand access to customized nucleic acid-based therapies.

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