Researchers Behind CRISPR Therapy Launching Clinical Trial for Rare Diseases

The researchers at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine behind the landmark customized CRISPR gene editing therapy that helped treat a patient’s ultra-rare metabolic disorder are planning an entirely new type of clinical trial to make this technology more accessible to patients with other rare diseases.

In a perspective piece published today in The American Journal of Human Genetics, Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at Children’s Hospital of Philadelphia and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, and Kiran Musunuru, MD, PhD, the Barry J. Gertz Professor for Translational Research in Penn’s Perelman School of Medicine, detail their experience in working with regulators to build upon their successful effort to develop a customized therapy for “Baby KJ” to treat severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a one in a million disease that is a type of urea cycle disorder, a group of rare disorders where the body cannot break down ammonia, causing a toxic buildup that can affect brain and liver.

Rather than use the same single-patient, expanded-access, “compassionate use” pathway that allowed KJ to receive his historic therapy, the researchers are actively working with agencies like the U.S. Food and Drug Administration (FDA) and the U.S. National Institutes of Health to launch clinical trials of personalized gene editing therapy platforms.

The therapy KJ received will not work for any other patient. However, switching out one small part of KJ’s therapy that acts like a “GPS of the genome” could allow it to correct many patient-specific variants causing liver-centered genetic disorders. Normally, each individual version of the therapy would be considered a totally new drug that would require lengthy and expensive studies to receive approval from the FDA for use in a clinical trial and, eventually, broad availability to patients. This has been a major obstacle in the development of therapies for ultra-rare diseases, with some so rare that there are only a handful of known patients worldwide, making a traditional clinical trial model not feasible.

In their interactions with the FDA since KJ’s treatment in February 2025—the records of which are being publicly released along with the perspective piece—the authors have reached agreement on the designs of “umbrella” clinical trials that can enroll patients with many different variants. All the versions of the gene editing therapy used to correct these variants would be considered a single drug, greatly streamlining the approval process. For example, the authors plan to launch a clinical trial in 2026 that can enroll patients with any of 7 different urea cycle disorders, caused by any variant in any of 7 genes that can be corrected by same type of gene editor used in KJ’s therapy. Successful treatment of a small number of participants—as few as 5-10, instead of the hundreds or thousands typically enrolled in clinical trials—might be sufficient for an FDA approval of the gene editing platform.

“We are optimistic that in the coming years, our team and other teams will be able to take tangible steps toward making interventional genetics the standard of care for many diseases,” the authors wrote.

Ahrens-Nicklas R and Musunuru K, “How to create personalized gene editing platforms: Next steps toward interventional genetics.”  Am J Hum Genet. Online October 31, 2025. DOI: 10.1016/j.ajhg.2025.10.006.

The researchers at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine behind the landmark customized CRISPR gene editing therapy that helped treat a patient’s ultra-rare metabolic disorder are planning an entirely new type of clinical trial to make this technology more accessible to patients with other rare diseases.

In a perspective piece published today in The American Journal of Human Genetics, Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program (GTIMD) at Children’s Hospital of Philadelphia and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, and Kiran Musunuru, MD, PhD, the Barry J. Gertz Professor for Translational Research in Penn’s Perelman School of Medicine, detail their experience in working with regulators to build upon their successful effort to develop a customized therapy for “Baby KJ” to treat severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a one in a million disease that is a type of urea cycle disorder, a group of rare disorders where the body cannot break down ammonia, causing a toxic buildup that can affect brain and liver.

Rather than use the same single-patient, expanded-access, “compassionate use” pathway that allowed KJ to receive his historic therapy, the researchers are actively working with agencies like the U.S. Food and Drug Administration (FDA) and the U.S. National Institutes of Health to launch clinical trials of personalized gene editing therapy platforms.

The therapy KJ received will not work for any other patient. However, switching out one small part of KJ’s therapy that acts like a “GPS of the genome” could allow it to correct many patient-specific variants causing liver-centered genetic disorders. Normally, each individual version of the therapy would be considered a totally new drug that would require lengthy and expensive studies to receive approval from the FDA for use in a clinical trial and, eventually, broad availability to patients. This has been a major obstacle in the development of therapies for ultra-rare diseases, with some so rare that there are only a handful of known patients worldwide, making a traditional clinical trial model not feasible.

In their interactions with the FDA since KJ’s treatment in February 2025—the records of which are being publicly released along with the perspective piece—the authors have reached agreement on the designs of “umbrella” clinical trials that can enroll patients with many different variants. All the versions of the gene editing therapy used to correct these variants would be considered a single drug, greatly streamlining the approval process. For example, the authors plan to launch a clinical trial in 2026 that can enroll patients with any of 7 different urea cycle disorders, caused by any variant in any of 7 genes that can be corrected by same type of gene editor used in KJ’s therapy. Successful treatment of a small number of participants—as few as 5-10, instead of the hundreds or thousands typically enrolled in clinical trials—might be sufficient for an FDA approval of the gene editing platform.

“We are optimistic that in the coming years, our team and other teams will be able to take tangible steps toward making interventional genetics the standard of care for many diseases,” the authors wrote.

Ahrens-Nicklas R and Musunuru K, “How to create personalized gene editing platforms: Next steps toward interventional genetics.”  Am J Hum Genet. Online October 31, 2025. DOI: 10.1016/j.ajhg.2025.10.006.