The First Personalized Gene Editing Treatment in an Infant

On February 25, 2025, a seven-month-old infant named KJ received the first infusion at Children's Hospital of Philadelphia (CHOP) of a treatment designed specifically for him—and for him alone. Not a standard medication, not a standardized protocol: a gene editing therapy manufactured in six months from the precise mutation identified in his genome. One year later, KJ walks and talks. His case, published in the New England Journal of Medicine in May 2025, has changed the trajectory of precision medicine and pushed the FDA to review its approval frameworks for individualized therapies.

What makes this case particular is not only the technology used—base editing derived from CRISPR—but the logic underlying it: manufacturing a drug for a single patient, based on his own mutation, within a timeframe that would have seemed impossible five years ago. This approach, called "N-of-1" therapy (for one individual), opens a path that medicine had been exploring theoretically for decades without having the tools to make it practicable.

A rare metabolic disease with 50% infant mortality

KJ was born with a severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a liver enzyme essential to the urea cycle. Without it, ammonia accumulates in the blood instead of being converted to urea and eliminated. This accumulation is neurotoxic: it can cause severe brain lesions, coma, and death. The estimated mortality for severe forms of this deficiency reaches 50% in early childhood, according to NIH data.

Before the era of gene therapy, therapeutic options were limited to very restrictive protein-restricted diets, nitrogen-scavenging medications to facilitate ammonia elimination, and, in the most critical cases, liver transplantation. These treatments allow managing the disease, not correcting it. They constrain 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 of developing treatments for rare genetic diseases—the market is too narrow to justify conventional pharmaceutical industry investments, and randomized clinical trials are impossible due to insufficient patient numbers.

Six months of development: from mutation to medication

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 COVID-19 mRNA vaccines, which deliver the treatment directly to liver cells.

From diagnosis to first infusion: six months. This timeline, which would have been unthinkable ten years 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 enabled mobilizing resources without waiting for usual commercial circuits.

The CHOP and Penn Medicine team, 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 infusions, and conducted preliminary safety tests—all in six months.

KJ received three infusions between February and April 2025. The publication in the New England Journal of Medicine in May 2025 described preliminary results. One year after the first infusion, CHOP published an assessment: no serious side effects, remarkable tolerance, and measurable clinical improvements.

Measurable clinical results after one year

The monitoring indicators are precise. KJ now tolerates a higher amount of dietary protein than before treatment—a direct marker of improved CPS1 function. His dependence on nitrogen-scavenging medications has been reduced by half. His ammonia levels remain better controlled even during common infectious episodes, which traditionally constitute the most dangerous moments for patients with urea cycle disorders.

Dr. Rebecca Ahrens-Nicklas, director of the gene therapy program for inherited metabolic diseases at CHOP, summarized the situation: "While this treatment is not a cure, after three infusions from February to April 2025, KJ has tolerated it well without serious side effects. He can manage more dietary protein, requires fewer nitrogen-scavenging medications, and we observe better control of ammonia levels during colds and other childhood illnesses."

KJ walks and talks. 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 evaluate the durability of the therapeutic effect and the absence of late effects—notably a possible 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 renews itself, the therapeutic effect could diminish, 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 framework called "plausible mechanism" 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 could suffice for platform approval, according to BioPharmaDive.

This regulatory evolution is significant. It recognizes that the paradigm of classic clinical trials—designed to evaluate mass-market drugs—does not apply to N-of-1 therapies. It paves the way for a multiplication of personalized treatments for rare genetic diseases, of which approximately 7,000 forms are cataloged, 95% of which have no approved treatment.

The regulatory issue goes 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 with the same rare diseases.

Access equity: the question that KJ's success does not resolve

KJ's treatment mobilized considerable resources: months of work by specialized teams, industrial partnerships, 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 health systems remains open.

Nature asked the question directly in a May 2025 article: "Personalized gene therapy helped one baby: can it scale?" The answer is nuanced. Development costs could decrease as platforms standardize and manufacturing processes industrialize. But absolute personalization—one drug for one patient—implies incompressible costs that do not follow usual economies of scale.

Existing approved gene therapies—like Zolgensma for spinal muscular atrophy or Casgevy for sickle cell disease—cost between $2 and $3 million per patient. An N-of-1 therapy, developed for a single individual, could cost more, even if platform economies reduce part of the costs. The question of who pays—insurance companies, public health systems, families—is not resolved.

KJ's parents, Kyle and Nicole Muldoon, chose to make their story public precisely to draw attention to these questions. They advocate for lawmakers to support funding for rare disease research and facilitate access to gene therapies for families who don't have the chance to live 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 timelines compatible with clinical urgency. The next step will be to make this approach accessible—financially, geographically, regulatorily—to a larger number of patients with rare genetic diseases for which no treatment exists today.

Approximately 300 million people worldwide are affected by a rare disease. The vast majority do not have access to curative treatment. KJ's case shows that personalized gene editing can, under certain conditions, fill this gap. But the conditions—specialized teams, funding, adapted regulatory infrastructure—are currently met in a very limited number of centers worldwide.

Main sources: Children's Hospital of Philadelphia — New England Journal of Medicine — NIH — Nature — BioPharmaDive

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