It’s been less than six months since the news of Baby KJ broke, a watershed moment for precision medicine with the first successful demonstration of a personalized in vivo gene-editing therapeutic. But for Becca Ahrens-Nicklas, MD, PhD, the physician who cared for KJ, and Kiran Musunuru, MD, PhD, the cardiologist and gene-editing researcher who designed the therapy, that single success was the requisite first domino to fall in the journey to developing approved gene-editing therapies for the countless other individuals with monogenic inherited diseases.
What unfolded at the Children’s Hospital of Philadelphia (CHOP) in 2025 was at once a singular act of medical innovation and the beginning of a deliberate, systems-level effort to make such feats reproducible. The treatment of KJ was carried out under what regulators call a single-patient expanded-access IND, a compassionate-use pathway designed for critically ill patients with no alternatives. “For KJ, what we did was what was called an expanded access, single-patient investigation on a new drug application, or IND for the FDA,” Ahrens-Nicklas told Inside Precision Medicine. “It’s clinical care,” she emphasized. “It’s not formal research—it’s designed to help a patient.”
Still, everyone involved knew that one patient, no matter how miraculous the outcome, could not be the endpoint. The question became: How do you turn a one-off rescue into a repeatable, scalable, and eventually reimbursable form of medicine? “While we were really excited that everything seemed to work well and safely with KJ, we knew we really needed to figure out a way to evaluate this in a formal clinical trial,” Ahrens-Nicklas said.
For the CHOP team, that meant building an entirely new clinical-trial framework—one that could take a customized therapy designed in weeks for a single child and evaluate it in a way regulators, insurers, and health systems could trust.
From one patient to many
Traditional drug development assumes a single drug tested in hundreds or thousands of patients. But in rare diseases, there are often only a handful of people worldwide with the same mutation. “In the world of rare diseases there are so many private variants that cause disease that are really only seen in one family or one very small population,” Ahrens-Nicklas said. “We have to have the flexibility to be able to adapt this without a long regulatory process.”
That flexibility would depend on a core scientific constant—a platform that stayed the same while allowing modular personalization. For Musunuru, who has spent years refining CRISPR-based tools for use inside the body, the path forward was clear: design a system where only one small genetic component, the guide RNA (gRNA), changes for each patient, while the rest—the lipid nanoparticle (LNP) delivery vehicle and the editor mRNA—stays constant.
“The reason we are targeting the liver,” Musunuru told Inside Precision Medicine, “is that standard LNP formulations preferentially accumulate there. If you want LNPs to go somewhere else, you have to do heroic things. The reason we have focused on the liver is two-fold: one, how to get to the liver. But more importantly for patients when you can make a fix in the liver, you can get great clinical improvement.”
That biological rationale dovetailed perfectly with clinical and regulatory needs. The liver is accessible, measurable, and medically crucial—particularly in metabolic diseases where a small correction can have outsized effects. “Because if the first one is benefiting the patient,” Musunuru said, “then certainly a liver-directed gene-editing therapy should have the potential to do as much good, but arguably with a much better safety margin and at less expense in the fullness of time.”
The treatment for KJ had used an LNP-delivered base editor to correct a pathogenic mutation in hepatocytes. The idea now was to take that same architecture and apply it to other liver-based monogenic disorders. Each new therapy would require a new gRNA targeting a different gene or variant, but everything else—the chemistry, formulation, manufacturing process, and delivery—could stay the same. The challenge was how to test not one therapy but a family of related ones under a single framework.
Under my umbrella
The CHOP team drew inspiration from oncology, where “basket” and “umbrella” trial designs allow flexibility within a single protocol. An umbrella trial, as described by Janet Woodcock, MD, is a type of clinical trial that evaluates multiple targeted therapies within a single disease, which is divided into subgroups based on specific biomarkers or other defining characteristics. Unlike traditional trials that test one drug for one condition, umbrella trials assess several therapies simultaneously within the same disease framework, assigning patients to different sub-studies or “strata” according to their biomarker profiles.
Operating under a unified master protocol—a feature shared with basket trials—this approach increases efficiency by streamlining infrastructure and enabling precision medicine strategies tailored to individual molecular or genetic features. Many umbrella trials are also adaptive, allowing researchers to modify the design in response to emerging data, thereby maintaining scientific rigor while accelerating the path to effective, personalized treatments.
They started with phenylketonuria (PKU), a classic metabolic liver disorder caused by mutations in the PAH (phenylalanine hydroxylase gene) gene. “We started with PKU it’s one disease the subgroups are the patients who have different variants. You really can consider it one drug entity,” Musunuru said. But they soon realized the same approach could reach far more patients if the framework were expanded. “We decided to get more ambitious,” he added. “What about urea-cycle disorders? Different genes but they’re all centered in the liver.”
The plan was to create a master protocol that could enroll patients across several urea-cycle disorders—technically distinct diseases but biologically and therapeutically related—under a single umbrella trial. “We could have any patient with any of the seven diseases that are amenable to correction enrolled in that trial,” Musunuru explained. The FDA, he said, was “agreeable to the idea that if you do five subjects across at least three of the seven diseases, we can have an end-of-Phase-II meeting and discuss an extension to Phase III.”
It was, as Musunuru put it, “pretty new ground that we’re trying to break here.”
Building the blueprint
Ahrens-Nicklas and Musunuru’s conversations with the FDA were not just about what could be done scientifically, but how it could be done repeatedly. “The master clinical protocol should go into the first IND for the first gene of interest,” Ahrens-Nicklas said. “Then as we have a patient ready for the second gene, we file a second IND, but we just cross-reference everything from the first IND. The only thing in that new IND are the things specific to that variant version of the drug.”
The first IND, in other words, serves as a parent file. Each new variant or gene-specific therapy references the original IND document, utilizing the same safety, manufacturing, and delivery data. “They are on board with that now,” Musunuru said. “That took some doing. For everyone in the field, there’s a pretty good consensus that this is one drug entity.”
The FDA also agreed that repeating toxicology studies in animals for every new variant was unnecessary. “What we agreed with the FDA is that we do not need to do any animal studies,” Musunuru said. “Once the initial toxicology study qualifying the LNP drug has been performed, we will not have to do that going forward. We have good agreement that using hepatocytes engineered to have a particular variant is sufficient.”
This change—allowing in vitro testing in human cells instead of new animal studies for every iteration—was transformative. It reduced cost and time dramatically, making the prospect of on-demand therapies feasible for small patient populations.
Ahrens-Nicklas underscored the long-term vision: “The only way you can do that is through the rigorous clinical trial, such that someday an insurance company will pay for a drug.” Musunuru added, “The real key is approval. Because once there is an approval, insurance companies will be open to reimbursing this treatment. That would make it self-sustaining.”
The new framework doesn’t just streamline regulation—it changes how patients and researchers interact. “If a physician has a patient they refer, we pre-screen: de-identified genetic info,” Ahrens-Nicklas said. “Then we work in the laboratory to find an effective solution for that variant in human cells. If we can find a good solution, then we can do formal screening inclusion/exclusion criteria and then enrollment.”
This process turns what once took years into something potentially achievable within months. Each patient’s therapy is individualized at the molecular level but standardized in every other respect—an inversion of traditional drug development. “For many of these families,” Ahrens-Nicklas said, “there are so many unknowns; it can be very daunting. So we hope that having this example will provide a template that other groups could follow.”
Beyond the liver and across borders
Despite the excitement, both scientists are cautious about the ethical stakes. “How do you make a well-thought-out, informed decision without that emotional tug of trying to save your kid?” Ahrens-Nicklas said. “This is something we are constantly trying to improve.”
Starting with urea-cycle disorders was a deliberate choice. “One reason we began with urea-cycle disorders,” she said, “is the current gold standard is a liver transplant. If experimental therapy doesn’t work, rescue therapy would be the liver transplant. So there’s a little safety net.”
Funding, however, remains a limiting factor because there haven’t been many takers in footing the bill for individualized treatments that don’t lead to commercializable products. Pooling diseases under a single trial may help. Shared infrastructure means lower cost per therapy and greater efficiency, a model that could make rare-disease development economically viable.
Musunuru also stressed the importance of global alignment. “Just because we get something through the FDA, it doesn’t mean we can start treating patients in the U.K. or Europe,” he said. “So part of our intent is to provide ammunition to our colleagues in other countries.”
For now, the immediate goal is modest but crucial: launch the first formal trial under this framework. “It’s going to be a single-site trial,” Ahrens-Nicklas said. “Multisite trials are much more resource intensive.”
The FDA has indicated that conditional approval could be possible with surprisingly small numbers. “If you do five subjects and treat them and you have a good safety profile,” Musunuru said, “then you can apply for conditional approval; the number that has been publicly stated is as few as five patients.”
Such a path, once considered impossible, now seems achievable. “The responsibility is on us,” Ahrens-Nicklas said, “to not make it about one baby but to rather make it about trying to help a population of sick kids.”
If successful, this approach could extend beyond liver diseases. “At least for now,” Musunuru said, “we would be doing the single toxicology study, then using a different base editor or prime editor, and then that would be another platform, which you think is important.”
Each new editing system—base, prime, or nuclease—could form its own regulatory backbone. Within those, personalized therapies could be developed rapidly, moving precision medicine from a bespoke miracle to a repeatable system. The architecture built for liver diseases might one day guide editing strategies for muscle, brain, or lung, once delivery vehicles evolve to reach them.
For all its complexity, the story began with a single child whose life depended on a bold, untested intervention. Yet both Ahrens-Nicklas and Musunuru see KJ’s case as the beginning, not the end. “It is not worth it for the rare-disease community and it doesn’t honor KJ if we don’t put the work in to actually get it done,” Ahrens-Nicklas said.
That work now extends beyond CHOP—to the FDA, to foundations funding early INDs, to scientists refining editing tools, and to families around the world hoping for a similar chance. If successful, the framework born from KJ’s treatment could mark the beginning of a new era in medicine: one where a therapy built for one becomes a pathway for all.
