In a remarkable medical breakthrough, KJ Muldoon was born last August with a potentially life-threatening genetic disorder known as CPS1 deficiency. Just six months later, he received a groundbreaking Crispr treatment specifically designed for him. This rare disorder can lead to dangerously high levels of ammonia in the blood, posing severe health risks — approximately half of infants diagnosed with CPS1 deficiency do not survive beyond early childhood. Traditional treatment methods, including a highly restrictive diet and liver transplantation, are far from ideal. However, a dedicated team from the Children’s Hospital of Philadelphia and Penn Medicine managed to circumvent the lengthy drug development process, creating a personalized medicine for KJ within months.
CPS1 deficiency arises when the body lacks an essential enzyme called CPS1, which is crucial for processing ammonia produced during protein digestion. Without this enzyme, ammonia accumulates in the bloodstream, leading to severe organ and brain damage, often resulting in death. Since KJ's birth, he has been on special medications aimed at reducing ammonia levels and has followed a low-protein diet. After receiving his custom Crispr therapy, KJ was able to reduce his medication dosage and start consuming more protein without experiencing significant side effects.
The case of KJ Muldoon, detailed in a study published in The New England Journal of Medicine and presented at the American Society of Gene & Cell Therapy annual meeting in New Orleans, may serve as a model for developing customized gene-editing treatments for other patients suffering from rare diseases that lack effective medical interventions. “We had a patient who was facing a very, very devastating outcome,” stated Kiran Musunuru, a professor of translational research at the University of Pennsylvania and a key member of KJ's treatment team. Following three doses of his personalized therapy, KJ has begun achieving developmental milestones that his family had previously thought unattainable.
In 2023, Ahrens-Nicklas and Musunuru focused their research on urea cycle disorders, a group of genetic metabolic conditions that impact the body's ability to process ammonia, including CPS1 deficiency. Traditionally, these conditions often necessitate liver transplants, which can be complex, especially for infants. When KJ was born, researchers employed genome sequencing to identify the unique genetic mutation causing his disorder, revealing that he had inherited two different mutations in the CPS1 gene—one from each parent. The team decided to target the mutation that had been previously reported in an unrelated patient known to have severe CPS1 deficiency.
The team utilized Crispr, the groundbreaking technology recognized with a Nobel Prize for its ability to edit DNA with precision. Although only one Crispr-based medicine is currently commercially available, targeting sickle cell disease and beta thalassemia, the potential of Crispr lies in its ability to address the root genetic causes of diseases rather than merely alleviating symptoms. The approved therapy, Casgevy, requires patients to undergo a complicated cell removal and editing process outside the body. However, KJ's therapy was specifically crafted to be redosable, starting with a low dosage to ensure safety.
Before administering the treatment to KJ, the researchers conducted safety tests in mice and monkeys. Given the experimental nature of the therapy, they sought and obtained permission from the Food and Drug Administration (FDA) to proceed with the treatment. After applying for approval on February 14, they received it just a week later, and KJ received his first dose on February 25. “The clinical responses described are impressive,” commented Timothy Yu, a neurologist at Boston Children’s Hospital, who was not involved in KJ's treatment. He praised the Philadelphia team’s meticulous and comprehensive approach.
The journey of personalized medicine continues to evolve, and KJ’s case highlights the potential for bespoke genetic treatments to be developed swiftly and effectively. However, both KJ's medical team and his parents are cautious in labeling the Crispr therapy a definitive cure. As noted by Rebecca Ahrens-Nicklas, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at the Children's Hospital of Philadelphia, while the therapy appears to have transformed KJ's severe deficiency into a milder form of the disease, he may still require ongoing medication.
The implications of KJ Muldoon's treatment extend far beyond his individual case. As Fyodor Urnov, scientific director at the Innovative Genomics Institute at UC Berkeley, notes, this case could serve as a blueprint for creating customized gene therapies for other patients suffering from rare diseases. Although the cost of producing KJ's therapy was not disclosed, it was comparable to the expense of a liver transplant, approximately $800,000. Both Musunuru and Urnov express hope that, with continued research and development, future patients with rare genetic disorders may no longer face premature death due to genetic mutations. “Though it will take a lot of work to get there, my hope is that someday no rare disease patients will die prematurely from misspellings in their genes,” Musunuru stated.
