The FDA is set to authorize “umbrella” clinical trials for rare diseases; the new approach will make the process faster and more sustainable by combining data from similar protocols, cutting redundant procedures, and reducing animal testing.

Thirteen years ago, the invention of CRISPR sparked enormous hope for treating countless diseases caused by genetic defects. Soon afterward, a growing number of clinical trials confirmed the revolutionary potential of this technology. But in recent years, confidence has faltered: attracting investors to the challenging field of rare diseases proved difficult, pushing many gene-editing companies to focus on a small handful of potentially lucrative areas — the most common “rare” disorders (starting with sickle-cell disease and thalassemia) or common genetic conditions such as cardiovascular diseases. A paradox emerged: the technological solution existed, but it often risked remaining confined to laboratories, far from patients.

Eventually, in May 2025, optimism surged again thanks to the record-speed development of the first bespoke CRISPR treatment for a newborn suffering from a severe metabolic disorder. Only a few months have passed since that breakthrough. In the meantime, Baby KJ has left the hospital, resumed metabolizing proteins, and is growing well. His story has become a catalyst for change, encouraging researchers and regulators to move beyond the status quo and open a smoother path toward testing — and hopefully approving — new therapies.

No one knows how much Baby KJ’s treatment would have cost if the public and private research centers involved had not worked on a non-profit basis throughout the six months required to develop it. However, this extraordinary collective effort seems destined to represent a turning point — a clear “before and after.” It is the first link in a chain of events that is expected to lead, in 2026, to the first clinical trial with adapted rules that can safely — and realistically — recruit and treat ultra-rare patients.

Instead of proceeding case by case, with individual compassionate-use authorizations — which would be prohibitively slow and expensive — small numbers of patients will be brought together under a single umbrella trial, even if they carry different mutations requiring slight adjustments to the therapeutic ingredients.

The announcement appeared on October 31 in The American Journal of Human Genetics, in an article by the two physicians who developed and administered Baby KJ’s treatment at the Children’s Hospital of Philadelphia (CHOP). Pediatrician Rebecca Ahrens-Nicklas and geneticist Kiran Musunuru explain how their work has helped shape a new horizon for CRISPR therapies by working with the FDA to simplify and rationalize the rules, aiming to move from bespoke treatment for a single individual (“N-of-one”) to tailor-made treatments for multiple individuals (“N-of-many”).

Their next steps include an umbrella trial for phenylketonuria, which can be caused by different mutations in the same gene (PAH), and another trial for infant-onset urea-cycle disorders, triggered by mutations in seven different genes (KJ’s case involved the CPS1 gene). They will use advanced CRISPR “base editors,” which chemically convert a single DNA letter to fix point mutations.

Normally, interactions between researchers developing innovative therapies and the regulators who grant experimental authorization remain confidential and are often covered by industrial secrecy. This time, however, anyone can peek inside the regulatory black box, because all communications — spanning months of negotiation to balance patient safety with the need not to block potential cures — have been made public, smoothing the way for other groups interested in launching similar clinical trials.

The core idea is that rules should remain strict for the first patient treated under an umbrella trial, but can become lighter for those who follow. The technological platform remains the same, and its safety is not undermined by small protocol changes used to guide the gene editor to a specific mutation.

For example, animal studies are needed to assess toxicity and biodistribution for the primary authorization, but if all goes well, they can be replaced with in vitro studies for similar requests within the same umbrella. The most important safety component is the lipid nanoparticles used to deliver the editor. For all patients in an umbrella study, their formulation is identical; what changes is mainly the small RNA molecule that identifies the target mutation.

After the success of KJ’s case, thousands of families with children affected by incurable genetic disorders have contacted the University of Pennsylvania and its children’s hospital. For many of them, CRISPR cannot yet help, because delivery systems capable of reaching the affected organ or tissue have not been perfected. But for children with liver diseases, as in KJ’s case, gene editing is already feasible. Turning this theoretical possibility into clinical practice is the only way to prevent patients with ultra-rare mutations from being discriminated against simply because their numbers are too small to attract sustainable business — a phenomenon Musunuru calls “mutational discrimination.”

Academic research does not answer to shareholders, so it is freer to explore every path. “We have the freedom, but also the moral obligation, to do it,” said Ahrens-Nicklas. Still, private industry will be needed: after inventing a treatment and having it approved, someone must manufacture and distribute it.

The Philadelphia team’s contribution is a “rising tide that lifts all boats,” as Fyodor Urnov told Nature. Urnov, who worked with Ahrens-Nicklas and Musunuru on the Baby KJ case, is ready to surf that wave: he has just become director of the first Pediatric Center for CRISPR Therapies, whose initial mission is to develop gene-editing therapies for eight young patients with congenital metabolic and immune disorders.

Another signal of optimism came in September from ARPA-H, the U.S. government’s Advanced Research Projects Agency for Health, which announced funding for two new programs to support the development and manufacturing of precision genetic medicines.

(translated from Le Scienze)