How to create personalized gene editing platforms: Next steps toward interventional genetics
- N1C Moderator
- 4 days ago
- 3 min read
December 4, 2025
Abstract
How do we go from a single individual receiving a personalized gene-editing therapy to a future of “interventional genetics” in which such therapies are the standard of care? First and foremost: regulatory innovation.
Main text
It has been discussed extensively elsewhere that the needs of the estimated 300 million affected individuals with rare and ultra-rare genetic disorders worldwide are poorly served by conventional drug development models, particularly with respect to gene-editing therapies that, in principle, could address the root cause of disease by correcting individuals’ pathogenic genetic variants—but these therapies would not be made because of their complexity and commercial considerations.1,2 In May 2025, we reported our work on behalf of an infant known as “KJ” in which a bespoke corrective gene-editing therapy for his severe urea cycle disorder (UCD), neonatal-onset carbamoyl phosphate synthetase 1 (CPS1) deficiency (MIM: 237300), was developed for one of his pathogenic CPS1 variants in 6 months. Following treatment under a single-patient expanded-access Investigational New Drug (IND) application to the US Food and Drug and Administration (FDA), there were signs of improvement.3 However, to robustly evaluate the safety and efficacy of this approach, formal clinical trials are needed. This example case has evidently helped to catalyze a plan by the FDA to create a “plausible mechanism pathway” for conditional approval of a platform of bespoke therapies with evidence of safety and efficacy from a small number of subjects (https://endpoints.news/new-fda-approval-pathway-for-n-of-1-therapies-coming-soon-prasad-says/), as well an announcement by the Advanced Research Projects Agency for Health (ARPA-H) of a new nine-figure set of funding opportunities for the purpose of “helping us go from saving one baby like KJ to saving thousands because every family deserves access to lifesaving treatment,” in the words of the Department of Health and Human Services Secretary (https://www.fiercebiotech.com/biotech/new-nine-figure-arpa-h-programs-seek-deliver-custom-gene-editing-treatments-more-patients). While these developments are encouraging, as is often the case, the devil is in the details.
We believe that pursuing a limited series of one-off compassionate-use single-patient INDs as part of clinical care—in contrast to formal clinical trials where the primary goal is acquisition of scientific knowledge that can be applied broadly—would be a disservice to the rare disease community. As such, we have been actively engaging with the FDA to flesh out the details of how to launch clinical trials of personalized gene-editing therapy platforms and ultimately seek regulatory approval for these platforms. These efforts take full advantage of the intrinsic programmability of CRISPR gene editors. KJ’s therapy comprised a lipid nanoparticle (LNP) formulation with an RNA encoding an adenine base editor (ABE) and a guide RNA specifying the genomic location of his pathogenic variant in CPS1; the LNPs largely target the liver, the primary site of the urea cycle. In principle, the same drug with changes only in the first 20 nucleotides of the guide RNA (which confer target site specificity) could correct many patient-specific variants causing liver-centered genetic disorders. Additional small changes to the ABE, e.g., to the protospacer-adjacent motif (PAM) preference and to the deaminase domain, could make a much larger set of variants accessible to treatment. Conceptually, a single platform could encompass all these small variations on the drug. A group of individuals with the same disease or with closely related diseases, but having a plethora of ABE-amenable pathogenic variants, could be enrolled in a single “umbrella” clinical trial.4
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