The first baby treated for a rare metabolic disease with CRISPR gives hope to thousands of patients.

Shortly after birth, KJ was diagnosed with an extremely rare and serious disease. His parents learned he had carbamoyl phosphate synthase (CPS1) deficiency, a condition that affects one in every 1,300,000 people. The deficiency disrupts the urea cycle, a bodily process that eliminates excess ammonia produced when we process proteins. Normally, our bodies convert ammonia into urea, which we excrete when we urinate, but KJ was missing an enzyme in his liver necessary for this conversion. When ammonia builds up, it can cause seizures with irreversible neurological damage and, in 50% of babies, death. In some cases, the disease can be treated with a liver transplant, but often babies are too small or have already suffered damage before surgery.

KJ was unlucky at birth, but then lucky. After spending the first six months of his life in the hospital, on a restrictive diet to avoid ammonia poisoning, in February of this year he received the first dose of a therapy that has changed his life. A team at the Children's Hospital of Philadelphia created a personalized gene therapy on an emergency basis, taking just six months from diagnosis to regulatory approval for compassionate use and its implementation. The drug precisely modified KJ's DNA to correct the mutation that was making him sick. A few months later, the baby is healthy and at home, and the results of this success were just presented in New Orleans (USA) at the annual meeting of the American Society for Gene and Cell Therapy and were published today, Thursday, in The New England Journal of Medicine .

To repair the malfunctioning genes, the researchers used CRISPR technology , which allows for precise cutting and pasting of DNA, specifically a version that makes it possible to edit the chemical bases that make up the letters of life's instruction book. With this editing system, they were able to correct errors of a single letter (a base) without completely cutting the DNA, and they were able to create a tailored therapy for the baby. The treatment was administered directly into KJ's body to target liver cells, where it was able to reach thanks to tiny fat capsules . These fat nanoparticles proved effective in introducing innovative medicines into the body with messenger RNA vaccines for COVID and have made possible treatments that previously failed due to lack of a means of transport.

The baby received two infusions of the treatment, at 7 and 8 months of age, and the results, according to doctors, are encouraging after seven weeks of follow-up, although they acknowledge that it is still a short time. Thanks to the therapy, KJ was able to increase the amount of protein he ate and reduce the medication he needed to eliminate nitrogen and keep his ammonia levels low.

The study shows that it is possible to rapidly develop and apply these types of personalized gene editing therapies to save the lives of those affected by these extremely rare diseases with unique variants. The authors believe this approach could be used to correct hundreds of inborn genetic errors that affect the liver and cause metabolic problems, but so far, success has only been achieved with one baby. Speaking to SMC Spain, Marc Güell, coordinator of the Translational Synthetic Biology research group and professor at Pompeu Fabra University (UPF), states that this is "a tremendous demonstration," but cautions that "this correction has been performed in the liver; other tissues are much more difficult to gene edit, for now."

“Years and years of advances in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he’s the first of many to benefit from a methodology that can be tailored to each patient’s individual needs,” said Rebecca Ahrens-Nicklas, MD, director of the Frontier Gene Therapy for Inherited Metabolic Disorders (GTIMD) Program at Children’s Hospital of Philadelphia and co-lead physician for the treatment.

Until now, gene-editing tools like CRISPR have been used to treat more common diseases affecting tens or hundreds of thousands of patients, such as the two diseases for which therapies are currently approved by European and US regulators: sickle cell anemia and beta-thalassemia. However, personalized gene-editing treatments benefit few of the patients suffering from these rare diseases, even though they collectively affect millions of people worldwide.

The results presented today, although only a first step and technical and cost challenges will have to be overcome, offer hope for those people. This hope has been fulfilled for Kyle Muldoon, KJ's father, who expressed his joy in a statement from the hospital: "We have been completely immersed in this since the boy was born, and our whole world has revolved around this little one and his hospital stay. We are so excited to finally be home together so KJ can be with his siblings, and we can finally breathe easy."