From One Patient to a New Paradigm: The Promise of N-of-1 Gene Therapies
On May 15, 2025, a groundbreaking article was published on the New England Journal of Medicine reporting a landmark in the history of medicine: the successful application of a personalized gene-editing therapy — using a novel base editing approach — to treat a young boy diagnosed with a fatal, previously untreatable genetic disorder.
The results, presented at the 2025 ASGCT Annual Meeting, mark a pivotal moment for the field of personalized medicine — especially for children with N-of-1 diseases, where time and innovation can mean the difference between life and death.
The patient, a 15-month-old boy referred to as KJ, had a rare metabolic condition known as Carbamoyl Phosphate Synthetase I Deficiency (CPS1D) — a urea cycle disorder that affects just one in 1.3 million babies. The condition prevents the body from eliminating ammonia from the bloodstream, leading to irreversible neurological damage or death if left untreated.
KJ’s parents, in search of options, connected with a team of researchers at the Children’s Hospital of Philadelphia (CHOP), who rapidly designed a CRISPR base editing strategy specifically targeting KJ’s unique mutation. The effort was led by scientists including Dr. Yann Jouvenot, Dr. Jennifer Doudna, and Dr. Beverly Davidson.
Following the personalized base editing treatment, KJ’s condition stabilized, and early signs suggest the therapy successfully reduced toxic ammonia levels in his blood, which is the hallmark of CPS1 deficiency. According to his medical team, he is now thriving — a dramatic shift from the grim prognosis he faced just months earlier. While long-term follow-up is ongoing, this case offers tangible proof that genome editing can be safely and effectively applied to treat even the rarest of disorders, one patient at a time.
“CPS1 deficiency is a devastating neonatal disease that affects the liver’s ability to detoxify ammonia. Without early intervention, it leads to irreversible brain damage or death,” explains Dr. Nicola Brunetti-Pierri, a clinician and researcher at TIGEM with expertise in urea cycle disorders, who — in a remarkable twist of fate — also trained at the Children’s Hospital of Philadelphia (CHOP), where KJ’s groundbreaking therapy was developed.
“Despite the fact that AAV-mediated gene therapy approaches are becoming increasingly effective tools to treat rare recessive disorders, the CPS1 gene is too large to fit into the packaging capacity of adeno-associated virus (AAV) vectors,” explains Dr. Nicola Brunetti. “This represented a major obstacle for the development of traditional AAV-based gene therapies for Carbamoyl Phosphate Synthetase I deficiency (CPS1D). For this reason, alternative strategies as base editing, antisense oligonucleotides, mRNA therapy, or custom AAV constructs had to be explored to overcome these technical challenges and advance toward clinical application.”
This news highlights what the scientific community has increasingly recognized in recent years as a critical unmet need: the ability to develop therapeutic solutions for patients with ultra-rare or even unique genetic diseases — conditions so rare that traditional clinical trials are not feasible due to the extremely small number of patients, yet they often involve life-threatening outcomes and no existing treatment options.
At TIGEM, we are committed to addressing this therapeutic gap. Since 2016, we established with Fondazione Telethon the Telethon Undiagnosed Diseases Program (TUDP). This initiative has been instrumental in identifying previously unknown genetic mutations in patients who lacked a genetic diagnosis, revealing an emerging population of individuals affected by nanorare mutations — ultra-rare genetic alterations not previously described in medical literature and for which no approved therapies exist. For these patients, a personalized therapeutic approach is not only appropriate — it is their only chance.
To meet this need, we also recently launched TIGEM’s N-of-1 program, with the mission to design individualized therapeutic tools based on the biological mechanism of each mutation. The program leverages our in-house research capabilities, clinical collaborations, and a multidisciplinary development path.
“Our goal is to create a scalable yet personalized pipeline to help those ultra-rare patients for whom no treatment is available,” explains Prof. Diego Di Bernardo, head of the Genomic Medicine Program at TIGEM and coordinator of the N-of-1 program. “We use high-throughput computational tools to assess which mutations are actionable, then test therapeutic hypotheses using cellular and animal models. Through our work with TUDP and our translational pipeline, we are aiming to uncover the hidden spectrum of genetic diseases that were previously invisible to both science and healthcare systems”.
However, science alone is not enough. The success of these programs — and of the patients they aim to save — also depends on regulatory systems that are flexible, responsive, and adapted to this new era of precision medicine. Today’s frameworks were built for therapies developed and tested in large cohorts, and are not designed to accommodate interventions tailored for a single patient or for conditions affecting just a few individuals worldwide. They urgently require rethinking.
Encouragingly, as also reported in the New York Times insight, the U.S. Food and Drug Administration (FDA) has acknowledged this gap and expressed readiness to engage with researchers and developers in creating new regulatory pathways that can safely and ethically support N-of-1 therapies. This marks a crucial shift — from a one-size-fits-all model to one that can accommodate individualized treatments based on solid scientific rationale.
TIGEM, together with Fondazione Telethon, aims to actively advocating for the creation of a fast-track, risk-adapted regulatory framework— one that reflects the scientific realities of N-of-1 therapy development and the urgency of acting for children with progressive, life-threatening diseases. As the field advances, regulators, scientists, clinicians, and families must work together to define a new ethical and clinical standard for what is possible — and permissible — in the treatment of rare diseases. And, as commented Stefano Benvenuti, Head of Fondazione Telethon Public Affairs, “together with a new regulatory framework, new economic models are necessary to systematically support the development of these therapies. We need to avoid the risk that individualized therapies become an option available only to those few families who can pay out of pocket for the development of the therapy their kids need and deserve”.
Conclusion: A New Standard of Possibility, and Responsibility
What once seemed like science fiction — designing and delivering a therapy for a single child — is now science fact. But it cannot remain an exception. The case presented at ASGCT 2025 and reported by the New York Times is a sign that the future of medicine is already here — and it must be scaled, supported, and regulated accordingly.
No disease is too rare. No patient is too alone. No case is too small to matter.