Response to the FDA’s proposed pathway for individualized genetic therapies

Timothy W. Yu, Julia Vitarello, Kiran Musunuru, Rebecca C. Ahrens-Nicklas, David R. Liu, Michelle L. Mellion, Fyodor Urnov, Winston Yan, Srinivas Chunduru, David Barrett, Terence R. Flotte, Janet Woodcock

January 7, 2026

Main text

The Food and Drug Administration (FDA) recently proposed a dedicated regulatory pathway for “personalized” therapies¹targeting genetic variation found in small numbers of individuals. This pathway is important, timely, and urgently needed. A number of such interventions have been investigated—e.g., milasen, a customized antisense oligonucleotide (ASO) drug designed for a child with Batten disease² that led to a series of individualized therapies for serious, ultra-rare neurogenetic diseases,³ and k-abe, a customized base editing therapy designed for an infant with CPS1 deficiency⁴—but no scalable or sustainable path for development has existed beyond research use supported by philanthropic or grant funding⁵. This framework is an important advance toward fulfilling the potential of targeted technologies (ASOs, CRISPR editing, gene replacement, etc.) to treat serious genetic diseases at their source. Since development programs for customized therapies will significantly differ from those for population-based interventions, consideration of implementation is critical.

Several key criteria are outlined for the “plausible mechanisms” pathway: the identification of a specific molecular or cellular abnormality, a medical product that targets the underlying and proximate biological alteration, a well-characterized natural history, confirmation (when possible) of target engagement, and improvement in clinical outcomes or course. While the form of the development programs required are not explicitly detailed, there are a number of possibilities. Investigational therapies involving a single chemistry (so-called platform technologies), route of administration, and with individualized variations in sequence could be studied under a single “umbrella” IND (sponsored by academia, industry, and/or non-profit organizations). Similarly, since the target is genetic rather than disease-focused, related types of mutations (e.g., genetic variants amenable to base editing, prime editing, splicing modulation, allele-selective knockdown, etc.) in related diseases (e.g., urea cycle disorders, severe inborn errors of immunity, or neurodegenerative conditions), could be studied together in a “basket” trial. Such trials would provide iterative learning, with results available after each intervention to inform next steps. An important objective of the clinical investigational stage would be standardization of all processes involved in the intervention, including procedures for identifying appropriate mutations, designing the individualized sequence, manufacturing, evaluating in vitro performance of candidates, conducting preclinical safety testing, and clinical administration and monitoring. As these processes are stabilized, their collective ability to produce a safe and effective intervention could be evaluated.

Evaluation of efficacy might include a comparison with external controls for certain disorders with well-understood natural history and biomarkers (e.g., urea cycle disorders), or might comprise serial self-controlled experiments with prospectively designated outcome measures for each individual (e.g., for conditions with high phenotypic heterogeneity). After an appropriate series of interventions, the probability of achieving a meaningful therapeutic response (e.g., changes in biomarkers and/or clinical assessments) and the profile of adverse events could be established for the standardized process. Sponsors could then submit a marketing application to the FDA.

If standards for quality, safety and effectiveness were met, FDA could approve a product that was the result of such standardized platform processes, despite the fact that the “product” would not be identical across mutations. After approval, patients meeting the standardized criteria could be treated without regulatory consultation. Sponsors seeking to alter the approved technology or route of administration would need to study the impact of such changes under a new IND. Mechanisms for long-term follow-up and addressing residual concerns would be dealt with as post market commitments, as usual, and manufacturing facilities would be subject to FDA oversight.

Continue Reading