CRISPR “n=1”: a new model for personalised therapy
A single-patient CRISPR therapy challenges how we define drugs, clinical trials, and regulation. Beyond clinical success, it signals a structural shift in medicine.
From a remarkable case to a structural turning point
The Brief Report, led by investigators including Kiran Musunuru, describes patient-specific in vivo base editing in a child with neonatal-onset carbamoyl-phosphate synthetase 1 (CPS1) deficiency, a devastating urea-cycle disorder associated with high early mortality. For these patients, liver transplantation remains the only definitive therapeutic option, often preceded by repeated hyperammonaemic crises and irreversible neurological injury. In this context, the partial biochemical correction observed after treatment is clinically meaningful. Yet the broader relevance of the report lies less in the individual outcome than in what it represents structurally.
What distinguishes this case is the unprecedented compression of the entire therapeutic trajectory. Within approximately six months from birth, investigators progressed from genetic diagnosis to the design, validation, manufacture and clinical administration of a bespoke CRISPR base-editing therapy under an expanded-access regulatory framework. Commentaries following publication have consistently underlined that this should not be interpreted as an isolated success story. Rather, it demonstrates that the traditional separation between research, manufacturing and clinical care can be collapsed into a single, tightly coordinated process.
The key innovation was not simply the use of base editing or lipid nanoparticles, but the operational model itself: a modular therapeutic platform in which delivery chemistry, mRNA backbone and much of the toxicology framework are shared, while only the guide RNA is customised to the individual pathogenic variant. In this sense, the CPS1 case reframes gene therapy from a fixed product into a reproducible, patient-triggered process.
The choice of the liver as the therapeutic target was strategic: the natural tropism of lipid nanoparticles (LNPs) toward hepatocytes facilitated delivery, bypassing one of the most significant hurdles in systemic gene editing.
Rewriting drug development
This conceptual shift has immediate implications for how therapies are evaluated and authorised. Conventional drug-development paradigms, built around large randomised trials and population-level efficacy endpoints, are poorly suited to interventions explicitly designed for a single individual. Regulators have been confronting this challenge for several years, informed by earlier experience with patient-customised antisense oligonucleotide therapies, but the CRISPR “n=1” case reported in NEJM has brought renewed urgency to the discussion.
In regulatory analyses published after the study’s release, particular attention has been paid to emerging frameworks such as so-called “plausible mechanism” pathways, in which a strong mechanistic rationale, validated biomarkers and intensive post-treatment surveillance may partially substitute for traditional efficacy trials in ultra-rare diseases.
Scientific commentators have also stressed the importance of methodological transparency. The detailed disclosure of off-target nomination and validation strategies, non-human-primate toxicology studies and the rationale for cautious dose escalation has been cited as essential for credibility. At the same time, several experts have urged caution in extrapolation. The CPS1 case benefited from favourable conditions, including liver-restricted delivery, a well-defined metabolic endpoint and the reversibility of lipid nanoparticle exposure, which allows for potential redosing.
These features may not apply to neurological or multisystem disorders. As highlighted in post-publication commentary, scalability will depend less on the evolution of CRISPR chemistry itself than on the development of reusable regulatory, analytical and manufacturing templates.
The importance of collaboration
Another recurring theme in expert reactions concerns institutional infrastructure. The success of this case relied on close coordination between academic gene-editing centres, hospital-based manufacturing facilities, specialised ethics committees and regulators willing to engage in real-time dialogue. Observers have contrasted this ecosystem-based approach with the commercial gene-therapy model of the past decade, in which development timelines often exceeded the clinical window of opportunity.
Public–academic initiatives, including large collaborative genome-editing consortia, have been identified as potential enablers of future “n=1” therapies by providing shared standards for vector design, off-target analysis and long-term follow-up.
Opportunity, limits, and responsibility
For most clinicians, the immediate relevance of an “n=1” CRISPR therapy does not lie in its imminent availability, but in how it reshapes expectations around incurability, prognosis and innovation. Expert reactions to the CPS1 report in The New England Journal of Medicine have consistently emphasised caution. Follow-up remains short, long-term oncogenic or immunological risks are unknown, and access will initially be restricted to a limited number of highly specialised centres. At the same time, few doubt that the conceptual shift is irreversible. Once a workflow exists that can move from genomic diagnosis to targeted molecular correction within months, expectations from patients and families affected by ultra-rare diseases will inevitably change.
This development places new responsibility on clinicians as mediators between rapidly evolving technology, regulatory uncertainty and patient communication. Familiarity with concepts such as base editing, lipid nanoparticle redosing, off-target nomination assays and expanded-access regulatory pathways will no longer be confined to molecular geneticists.
As several commentators have noted, the central challenge of the coming years will not be whether personalised gene editing is technically possible, but whether healthcare systems can integrate such bespoke therapies in a way that is scientifically robust, ethically defensible and socially equitable. The CRISPR “n=1” case thus stands less as a promise of immediate cures than as a signal that medicine is entering an era in which manufacturing itself becomes personalised - and in which clinicians must be prepared to navigate this transition with both scientific literacy and restraint.
- Musunuru K, Grandinette SA, Wang X, Hudson TR, Briseno K, Berry AM, Hacker JL, Hsu A, Silverstein RA, Hille LT, Ogul AN, Robinson-Garvin NA, Small JC, McCague S, Burke SM, Wright CM, Bick S, Indurthi V, Sharma S, Jepperson M, Vakulskas CA, Collingwood M, Keogh K, Jacobi A, Sturgeon M, Brommel C, Schmaljohn E, Kurgan G, Osborne T, Zhang H, Kinney K, Rettig G, Barbosa CJ, Semple SC, Tam YK, Lutz C, George LA, Kleinstiver BP, Liu DR, Ng K, Kassim SH, Giannikopoulos P, Alameh MG, Urnov FD, Ahrens-Nicklas RC. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025 Jun 12;392(22):2235-2243. doi: 10.1056/NEJMoa2504747. Epub 2025 May 15. PMID: 40373211.