The first patient of personalized in-vivo gene editing therapy
Quick Summary
- In August 2024, baby KJ was born in Philadelphia with a rare and life-threatening genetic condition: CPS1 deficiency.
- In KJ’s treatment, his team used a variation of CRISPR editing called base editing where one single faulty base (like a single letter misspelt in a sentence) of DNA is cut out and corrected.
- It marks the beginning of a new era of personalized medicine and gene-editing therapies, where precise gene-editing tools can be used to create treatments tailored not just to a disease, but to an individual patient.
In August 2024, baby KJ was born in Philadelphia with a rare and life-threatening genetic condition: CPS1 deficiency. A mutation in his DNA meant he lacked a liver enzyme (CPS1) that breaks down ammonia–a waste product of protein metabolism. Patients with CPS1 deficiency need liver transplants, and to do so they need to be medically stable and old enough to handle a transplant procedure. In the meantime, there runs a risk of ammonia levels building up in the body and damaging organs, particularly the brain and liver. For infants like KJ, this disease carries an estimated 50% mortality rate.
For the first several months, his treatment included a restrictive diet, dialysis and medication to control ammonia levels. But, in February 2025, KJ would become the first patient of personalized in-vivo gene-editing therapy (gene-editing delivered to and done directly in the body as opposed to modifying the cells outside the body and then reinfusing).
Dr. Rebecca Ahrens-Nicklas and Dr. Kiran Musunuru began the groundwork for this breakthrough in 2023 when they began developing customized gene editing therapies and focused on urea cycle disorders (like in KJ’s case). After KJ’s specific mutation was identified, Ahrens-Nicklas and Musunuru alongside an international team spanning academia and industry took only six months and created a CRISPR gene-editing therapy delivered by lipid nanoparticles to the liver to rewrite KJ’s faulty enzyme. CRISPR is a gene-editing tool that acts like a targeted pair of scissors to our DNA. In KJ’s treatment, his team used a variation of CRISPR editing called base editing where one single faulty base (like a single letter misspelt in a sentence) of DNA is cut out and corrected.
The results have been promising. KJ has had no serious side effects and has been able to tolerate increased dietary protein, has required less medication and has begun reaching developmental milestones. While he receives long-term care to monitor his condition and the effects of his treatment, his progress offers hope and a path for similar procedures to treat rare diseases for which adequate medical treatments are not yet available. Currently, researchers have created one FDA-approved CRISPR-based therapy, for sickle cell disease and beta thalassemia. However, individuals with rare genetic diseases often have a highly specific mutation and a one-size-fits-all approach doesn’t fit them.
In order for KJ to receive his first-of-its-kind therapy, researchers had to use the single-patient expanded access/“compassionate use” FDA pathway which allows single patients with life-threatening conditions to access treatments outside the standard clinical trial when no satisfactory treatments exist. Normally, each such individualized therapy would be considered a different treatment requiring lengthy large-scale clinical trials before they become widely available. However, this is an issue for rare and ultra-rare diseases as only a small population of patients exist worldwide. This case helped catalyze a new FDA regulatory pathway, the “plausible mechanism pathway”, for approval of individualized treatments like KJ’s. The new pathway allows for the conditional approval of personalized therapies with evidence of its safety and efficacy collected from a small number of subjects. A product targetting different mutations on the same gene could be included in a single application and potentially be evaluated in a single trial. These small trials may provide sufficient support to file a marketing application. Following approval, evidence of the efficacy of the therapy and the lack of off-target editing in those treated must be collected.
The FDA ensures maintaining scientific rigor, safety and efficacy through five key requirements:
1. A clearly defined genetic, cellular or molecular basis for the disease.
2. A therapy that directly targets the underlying molecular alteration that causes disease.
3. A well-understood natural history of the disease in the untreated population.
4. Evidence that the biological target was successfully modified.
5. Meaningful clinical improvement of the patient.
KJ’s story is more than a medical success story. It marks the beginning of a new era of personalized medicine and gene-editing therapies, where precise gene-editing tools can be used to create treatments tailored not just to a disease, but to an individual patient.
Sources:
https://www.nature.com/articles/d41586-025-03847-2
https://innovativegenomics.org/news/first-patient-treated-with-on-demand-crispr-therapy/
https://www.cell.com/ajhg/fulltext/S0002-9297(25)00397-0
https://www.synthego.com/blog/dissecting-the-fdas-plausible-mechanism-pathway/