The First Personalized Gene Editing Treatment in an Infant
# The First Personalized Gene Editing Treatment in an Infant
On February 25, 2025, a seven-month-old infant named KJ received the first infusion of a treatment designed specifically for him—and for him alone—at the Children's Hospital of Philadelphia (CHOP). Not a mass-produced drug, nor a standardized protocol: a gene editing therapy manufactured in six months based on the precise mutation identified in his genome. A year later, KJ is walking and talking. His case, published in the *New England Journal of Medicine* in May 2025, has altered the trajectory of precision medicine and prompted the FDA to review its approval frameworks for individualized therapies.
What makes this case unique is not only the technology employed—CRISPR-derived base editing—but the underlying logic: manufacturing a drug for a single patient, based on their own mutation, within a timeframe that would have seemed impossible five years ago. This approach, termed "N-of-1" therapy (for a single individual), opens a path that medicine had explored in theory for decades without the tools to make it practical.
A Rare Metabolic Disease with 50% Infant Mortality
KJ was born with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a liver enzyme essential for the urea cycle. Without it, ammonia accumulates in the blood instead of being converted to urea and excreted. This accumulation is neurotoxic: it can cause severe brain damage, coma, and death. The estimated mortality for severe forms of this deficiency reaches 50% in early infancy, according to data from the NIH.
Before the era of gene therapy, therapeutic options were limited to highly protein-restricted diets, nitrogen-scavenging medications to facilitate ammonia elimination, and, in the most critical cases, liver transplantation. These treatments manage the disease but do not correct it. They compel patients to permanent monitoring and repeated hospitalizations during infectious episodes, which can trigger potentially fatal hyperammonemic crises.
CPS1 deficiency is an orphan disease: it affects approximately 1 in 800,000 births. This figure illustrates the structural difficulty in developing treatments for rare genetic diseases—the market is too small to justify traditional pharmaceutical industry investments, and randomized clinical trials are impossible due to an insufficient number of patients.
Six Months of Development: From Mutation to Medicine
The technology used is not CRISPR-Cas9 in its classic form, which cuts both DNA strands. It is a base editor, a more precise version developed by David Liu at Harvard University starting in 2016. The base editor modifies a single letter of the genetic code without introducing a double-strand break—thus reducing the risk of unwanted mutations. This editor was encapsulated in lipid nanoparticles, the same vectors used for mRNA vaccines against Covid-19, which deliver the treatment directly to liver cells.
From diagnosis to the first infusion: six months. This timeframe, which would have been unthinkable a decade ago, was made possible by several converging factors. First, the maturity of base editing platforms, which allow targeting a specific mutation with high precision. Second, the availability of industrial partners capable of rapidly manufacturing the necessary components—Acuitas Therapeutics for lipid nanoparticles, Integrated DNA Technologies, and Aldevron for gene editor components. Finally, funding from the National Institutes of Health (NIH) and CHOP's Gene Therapy for Inherited Metabolic Disorders Frontier Program, which allowed for the mobilization of resources without waiting for usual commercial channels.
The team from CHOP and Penn Medicine, led by Dr. Kiran Musunuru, first sequenced KJ's genome to precisely identify the mutation responsible for his CPS1 deficiency. They then designed a base editor capable of correcting this specific mutation in liver cells, manufactured the components in sufficient quantity for the infusions, and conducted preliminary safety tests—all within six months.
KJ received three infusions between February and April 2025. The publication in the New England Journal of Medicine in May 2025 described the preliminary results. One year after the first infusion, CHOP published an update: no serious side effects, remarkable tolerance, and measurable clinical improvements.
Measurable Clinical Outcomes After One Year
Follow-up indicators are precise. KJ can now tolerate a higher amount of dietary protein than before treatment—a direct marker of improved CPS1 function. His dependence on nitrogen-scavenging medications has been halved. His ammonia levels remain better controlled even during common infectious episodes, which traditionally represent the most dangerous times for patients with urea cycle disorders.
Dr. Rebecca Ahrens-Nicklas, director of the Gene Therapy Program for Inherited Metabolic Disorders at CHOP, summarized the situation: "While this treatment is not a cure, after three infusions from February to April 2025, KJ tolerated it well with no serious side effects. He can manage more dietary protein, requires less nitrogen-scavenging medication, and we are seeing better control of ammonia levels during colds and other childhood illnesses."
KJ is walking and talking. For a disease whose severe form is associated with early neurological damage, these developmental milestones have real clinical significance. Long-term follow-up remains necessary to assess the durability of the therapeutic effect and the absence of late-onset effects—notably, a potential delayed immune response or loss of efficacy over time.
It is important to note that KJ's treatment is not a definitive cure. The base editor corrects the mutation in existing liver cells, but new cells produced by cell division do not carry the correction. As KJ grows and his liver regenerates, the therapeutic effect might wane, potentially requiring additional infusions.
The FDA Adapts Its Regulatory Framework for Individualized Therapies
KJ's case had an immediate effect on regulatory discussions in the United States. The FDA announced a new "plausible mechanism" framework for individualized therapies, designed to accelerate approvals in rare diseases where large-scale randomized clinical trials are structurally impossible—there simply aren't enough patients.
This framework proposes a platform approach: all versions of the same base editor targeting different mutations of the same gene would be treated as a single drug. A single trial could include patients with any of the seven urea cycle disorders that the same editor can correct. Positive results in 5 to 10 patients might be sufficient for platform approval, according to BioPharmaDive.
This regulatory evolution is significant. It recognizes that the paradigm of classical clinical trials—designed to evaluate mass-market drugs—does not apply to N-of-1 therapies. It opens the way for a proliferation of personalized treatments for rare genetic diseases, of which approximately 7,000 forms are identified, 95% of which have no approved treatment.
The regulatory challenge extends beyond the American case alone. In Europe, the European Medicines Agency (EMA) has not yet adopted an equivalent framework for N-of-1 therapies. This regulatory asymmetry could create access inequalities between American and European patients suffering from the same rare diseases.
Equity of Access: The Question KJ's Success Does Not Resolve
KJ's treatment mobilized considerable resources: months of work by specialized teams, industrial partnerships, and urgent public and private funding. This model is not directly reproducible on a large scale, and the question of the cost of N-of-1 therapy for public healthcare systems remains open.
*Nature* directly posed the question in a May 2025 article: "Personalized gene therapy helped a baby: can it be scaled?" The answer is nuanced. Development costs could decrease as platforms standardize and manufacturing processes industrialize. But absolute personalization—a drug for a single patient—involves incompressible costs that do not follow usual economies of scale.
Existing approved gene therapies—such as Zolgensma for spinal muscular atrophy or Casgevy for sickle cell disease—cost between 2 and 3 million dollars per patient. An N-of-1 therapy, developed for a single individual, could cost more, even if platform economies reduce some costs. The question of who pays—insurers, public healthcare systems, families—is not resolved.
KJ's parents, Kyle and Nicole Muldoon, chose to make their story public precisely to draw attention to these issues. They advocate for legislators to support funding for rare disease research and facilitate access to gene therapies for families who do not have the fortune of living near a cutting-edge research center.
A Step in a Long Trajectory
CRISPR-Cas9 was first described as a gene editing tool in 2012. Its origins date back to 1987, with the discovery of repeated sequences in the E. coli genome, whose role in bacterial immunity was only elucidated in the early 2000s. The first human clinical applications began in China in 2016. Base editing, a more precise version, was developed by David Liu at Harvard University starting in 2016 and published in Nature in 2017.
KJ's treatment is not the end of this trajectory, but a step in an acceleration. It demonstrates that precision medicine can now operate at the scale of a single individual, with timeframes compatible with clinical urgency. The next step will be to make this approach accessible—financially, geographically, regulatorily—to a wider number of patients with rare genetic diseases for which no treatment currently exists.
Approximately 300 million people worldwide are affected by a rare disease. The vast majority do not have access to a curative treatment. KJ's case shows that personalized gene editing can, under certain conditions, fill this void. But the conditions—specialized teams, funding, adapted regulatory infrastructure—remain for now met in a very limited number of centers worldwide.
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Main Sources: [Children's Hospital of Philadelphia](https://www.chop.edu/news/childrens-hospital-philadelphia-marks-one-year-anniversary-worlds-first-personalized-crispr) — [New England Journal of Medicine](https://www.nejm.org/doi/10.1056/NEJMoa2504747) — [NIH](https://www.nih.gov/news-events/news-releases/infant-rare-incurable-disease-first-successfully-receive-personalized-gene-therapy-treatment) — [Nature](https://www.nature.com/articles/d41586-025-03566-8) — [BioPharmaDive](https://www.biopharmadive.com/news/crispr-n-of-1-gene-editing-csp1-deficiency-nejm/748260/)
