In May, news broke of a biomedical first: the on-demand design and clinical use of a personalized gene editor for a baby boy born with a rare, severe genetic condition. At the STAT Summit in October, the child’s treating physician from the Children’s Hospital of Philadelphia (CHOP) and the lead on developing the gene editor for him shared the stage with him and his parents. The video of a happily squirming 1-year-old brought tears of joy to the eyes of many.
A sobering reminder of the long road ahead toward more such videos was shared in these pages by Celena Lozano, whose son lives with a no less rare and severe genetic condition called PURA syndrome. Concerned over false hope inadvertently created by exuberant media coverage of the success story, she wrote, “families of the rare disease community deserve to have a better understanding of when their child might be next.”
I am personally moved by her plea because work at my institution, the University of California, Berkeley’s Innovative Genomics Institute, focuses on developing personalized gene editors for severely ill children living with genetic diseases. One such child is Lucy Landsman, whose mom, Geri Landsman, shared her family’s story in the media.
Lucy’s disease, PGAP3 deficiency, also affects neurologic development, just like PURA syndrome. Lucy’s clock is ticking loudly, and she may start developing intractable seizures soon. My colleagues and I have designed a gene editor that efficiently repairs Lucy’s mutation in a laboratory experiment, and we are part of a cross-functional team working to advance to a clinical trial. With philanthropic and industry support, we have also done this for mutations severely affecting the quality of life of several other children on clinical service at our partner institution, University of California San Francisco.
As our physician colleagues there plan for clinical trials to start in 2026 using these gene editors, we are mindful of a dire truth: Even if every major teaching hospital in the U.S. launches such trials, collectively they will treat only a tiny fraction of children who need such treatment.
Encouragingly, over the past 13 years a branch of the cell and gene therapy field has made major strides in addressing this challenge. On April 17, 2012, a team at CHOP treated a 7-year-old girl named Emily Whitehead, who was dying of incurable leukemia, with an experimental personalized genetically engineered cell therapy known as CAR-T. Emily today is a thriving college student. In a victory for science, medicine, and health care economics, there are seven approved medicines of this type today, and more than 60,000 patients have received such personal gene therapies.
Let us count back from success and chart out a similar path for safe and effective CRISPR treatments on demand.
Here, the key phrase is “approved medicine”: A physician needs to be able to prescribe such a treatment for a child, a path must exist to manufacture and administer it, and the health care system needs to pay for it in some way.
As recently as September 2024, the path to such a future was nonexistent for 99.9% of all patients with a rare genetic disease because a given clinical trial for gene editing could only focus on repairing a single specific mutation, even in cases where different mutations in the same gene cause the same disease. That fragmented the community of people living with diseases into many thousands of clinical trials, forcing the for-profit sector to abandon clinical development in most genetic diseases. A gene editing trial for a prevalent disease-mutation combination, such as alpha 1 antitrypsin deficiency, which affects more than 3 million people globally, makes commercial sense. Targeting disease-causing mutations in CPS1, or PURA, or PGAP3 — or in approximately 5,900 other genes — does not.
How do we go from near-zero for-profit sector activity to multiple clinical trials?
In late 2024, Food and Drug Administration leadership brought together nine academic and for-profit clinic-bound gene editing teams to discuss how to “platformize CRISPR.” Participants in this workshop, including the IGI, truly “sang in 9-part harmony:” whether focused on urea cycle disease or severe inborn errors of immunity, the “ask” of the regulators from the teams was near-identical. If it takes X years and Y dollars to build a CRISPR on-demand for a mutation in a gene that affects a given child, then it should take much less time and be much less expensive to build such a CRISPR for a second child with a different mutation as long as both children have the same kind of disease and you’re making only small changes to the overall therapeutic.
For instance, you could safely omit redundant studies in animals that do not de-risk anything related to what you changed. The most important part is that building such a CRISPR for a third child with yet another mutation should be even cheaper and faster than for the second child, while maintaining safety.
As described two weeks ago by the team at CHOP and the University of Pennsylvania, driven by that dialog and the subsequent clinical success with treating a child in on-demand mode, the field has now taken a substantial step toward making this “CRISPR platformization” clinically real. There is now an actionable regulatory framework under which children with a given clinical syndrome can all be enrolled in the same clinical trial. CHOP is planning to start such an umbrella trial for urea cycle disease in 2026 and shared its relevant regulatory filings and correspondence with the FDA on the website of a federal program that funded this work. A joint IGI-UCSF team working on a clinical syndrome of severe T cell dysfunction has a conceptually congruent proposal under review at the FDA at the present time.
Should this succeed clinically, how will such medicines be approved?
In a perspective in the New England Journal of Medicine this week, FDA Commissioner Marty Makary and Vinay Prasad, the director of the branch of the FDA that regulates clinical gene editing, take a timely complementary step to all this nonclinical and clinical innovation. They propose granting approval to gene editing medicines made on-demand, i.e., where every child gets a slightly different gene editor, if 1) the medicine treats children with the same clinical syndrome (e.g., a particular metabolic disorder or a certain immune deficiency syndrome), no matter what the underlying mutation is, and 2) it shows consistent patient-to-patient efficacy of a scale that cannot be expected under standard of care.
The scientific rationale for this approach is sound: Gene-editing medicines such as was administered at CHOP function by directly repairing the specific genetic defect that causes the disease. There is no uncertainty as to why the medicine works — we have, in Makary’s and Prasad’s turn of phrase, a “plausible mechanism” for it. If the clinical effect is robust patient to patient, the FDA will consider granting approval after a trial with a small number of patients.
So when should a given family like Celena Lozano’s or Geri Landsman’s expect to reap benefit from any of this regulatory innovation?
For two sets of genetic diseases, namely those that can be treated by gene editing the liver or blood stem cells, the first FDA approvals could arrive as soon as three years from now. Initially these will be relatively few in number because at present time nearly all such “build a CRISPR medicine on-demand” work is taking place in academic settings: for instance at Penn-CHOP for metabolic diseases, at the University of Wisconsin for congenital blindness, and at IGI-UCSF, where our team has developed a path to treating severe inborn errors of immunity in an “umbrella trial” to begin in 2026.
Assuming clinical success and approval — how will patients gain access to such treatments?
My parental institution, the University of California, is not in the business of selling medicines, so one viable path is to establish a public benefit corporation. A clinical team at UCLA has done this for a gene therapy medicine for a severe pediatric immune deficiency. The key expectation is all this “academic” medicine will inspire the for-profit sector to take notice of the above and get in on the game. For instance, the biotechnology company Prime Medicine recently shelved a gene editing program to treat an immune deficiency that focused on a specific mutation in one gene. Prime could now approach a larger patient population by putting together an umbrella trial and aiming to treat any patient with the cognate clinical syndrome (i.e., any genetic defect of neutrophil function).
What about children living with diseases other than of the liver or hematopoiesis?
Based on the current state of technology there is now a clear divide between diseases affecting tissues and organs that are amenable to nonviral delivery (such as lipid nanoparticles or enveloped delivery vehicles) and those that are not and thus require adeno-associated virus (AAV) for delivery. In the case of the latter — which includes many children living with neurodevelopmental diseases such as PURA syndrome or PGAP3 deficiency — the likelihood of an approved “CRISPR on demand” medicine in, say, the next three to four years are low. This derives from a challenge that the field of AAV-based gene therapy has faced since the first trial with it in 1995: the complex requirements for manufacturing clinical-grade AAV.
Parents of children with rare diseases ask: How long until our CRISPR miracle?
Despite an enormous effort to make things faster and cheaper, the cost of one batch of such a virus is $2 million and the wait time is more than a year. This cannot be scaled in a setting where each patient would require a different gene editor-carrying virus.
For this reason, two actionable, viable genetic medicine paths are the use of antisense oligonucleotides to upregulate expression of the gene and gene addition therapy where the same AAV can be used for many patients. The stark truth is: Approved gene editor medicines for many severe neurologic diseases await a marked improvement in delivery technology.
That said, in addition to blood and liver there are other tissues/organs where nonviral delivery is clinically actionable. Here, the picture is different. An example is the lung, where multiple severe genetic diseases require an on-demand gene editor therapy and solid progress is being made with LNP-mRNA delivery.
In principle an effort in this space could follow a path such as the one reduced to regulatory practice by the CHOP-Penn effort in metabolic disease and pursued by IGI-UCSF and other academic groups: a “master clinical trial protocol” plus the “platform approach to manufacture and derisking a CRISPR on-demand.”
Where can this go wrong?
Gene editing technology itself is not the major obstacle over the next decade to innovative trials and approved medicines of this type. As I look at the trajectory of that space since first use of editing on human genes in 2005 by a team I was part of, our ability to repair a disease-causing mutation with clinic-grade potency and specificity has gone through an upgrade akin to the LP-to-Spotify one.
The obstacle is that existing regulatory requirements for making that gene editor for use as an approved medicine are based on treating thousands of patients. Unfortunately, a child at UCSF Health who weighs 10 pounds and has three months to live cannot benefit from a quantity of guide RNA sufficient to treat 1,000 adults that takes many months to manufacture.
Here, the IGI and Danaher Corporation teamed up to develop what we call “benefit-risk commensurate” accelerated small-scale manufacture. Broad use of these types of novel manufacturing frameworks will require regulatory flexibility from the FDA that is forward-integrated to multiple approved platform medicines under the “plausible mechanism pathway.”
The second biggest obstacle is the remaining lull in the for-profit sector. Returning to genetic diseases affecting the lung , many of the patients living with cystic fibrosis due to the “long tail” of mutations that cannot be remedied by small molecules (as reported in STAT) could now become the subjects in an umbrella trial for CRISPR-on-demand. Given the incidence and prevalence of cystic fibrosis, this is a commercially viable approach.
A path to such a trial is to start in a severe pulmonary syndrome (such as surfactant deficiencies) where some newborns die soon after birth, or primary ciliary dyskinesia where no disease-modifying therapies exist.
In principle, the new FDA developments are a roadmap: start with a small clinical trial in the severe indications, de-risk the delivery modality and small-scale CRISPR manufacture, advance to approval, and then leverage all the learnings into a CF program.
In practice, who is going to do that? The majority of for-profit entities in this space are not exactly cash-flush. Here, the public sector is, objectively, the best hope. The federal government has invested in a “CRISPR as a clinical platform” effort, the Somatic Cell Gene Editing Consortium, that in fact supported the work on CRISPR on demand. A recently announced ARPA-H program has more expansive goals. Such federal support is not a good to have — it’s essential in order to get the clinical validation of the new approaches that recent developments make possible. The U.K. government has similarly invested in a program of this type.
Three years ago, I wrote a piece in the New York Times titled “We Can Cure Disease By Editing a Person’s DNA. Why Aren’t We?” Rereading it today I am delighted by not merely quantitative but qualitative progress our field has made. Today, there is fresh wind in our sails. That said, in order to realize the promise of CRISPR — to give Celena Lozano’s and millions of families living with genetic diseases a better answer to the question “when will my child be next?” — we cannot rest on any laurels for even a fraction of a second.
Fyodor Urnov is a professor of molecular therapeutics at the University of California, Berkeley, and a director at its Innovative Genomics Institute.