First "tailored" genetic treatment for a baby's rare disease

BarcelonaLittle KJ was born less than a year ago with a rare disease that affects the metabolism of urea, a chemical compound normally excreted in urine. Children with this condition, known as severe carbamoyl phosphate synthase 1 (CPS1) deficiency, require a liver transplant, but must be stable and old enough to undergo such a complex operation. Since KJ didn't meet these requirements, he spent his first months of life at the Children's Hospital of Philadelphia on a very restrictive diet. During this waiting period, the buildup of ammonia can cause permanent neurological damage, and even death, so doctors tested a new approach, previously unheard of anywhere in the world. When he was 6 months old, he received the first dose of a gene-editing therapy called CRISPR, which can precisely correct alterations in the human genome, making him the first patient in the world treated with such a personalized therapy.

"Although KJ is just one patient, we hope he's the first of many to benefit from a technique that can be tailored to each patient's needs," says Rebecca Ahrens-Nicklas, director of the Pioneering Gene Therapy Program for Inherited Metabolic Disorders at the state hospital. The center's professionals published a study this Thursday in the journal The New England Journal of Medicine to verify the success of the intervention. The treatment they used is highly complex and, until now, has been used for more common diseases that affect tens or hundreds of thousands of patients, but patients with rare genetic disorders were excluded from these advances. In other words, a "tailored" approach for a single patient, as in the case of KJ, had never been developed.

The baby received the first dose last February and has been given follow-up doses in March and April. So far, he is doing well, although he will need lifelong monitoring. Still, the authors believe this goal may pave the way for gene-editing technology to be adapted to treat people with rare diseases for which there are currently no available treatments. "The promise of gene therapy that we have felt for decades is finally being realized, completely transforming the approach to medicine," says Kiran Musunuru, a professor at Penn's Perelman School of Medicine and co-author of the article.

For other diseases too

Two years ago, Ahrens-Nicklas and Musunuru began working together with the goal of creating personalized gene-editing therapies for a single patient. They leveraged all the available scientific evidence on rare metabolic disorders and the application of gene editing and decided to focus on urea cycle disorders like the one KJ had. When we break down proteins, we produce ammonia, which our bodies then convert into urea, but children with this disease cannot make the conversion, causing the ammonia to build up to toxic levels and cause damage, particularly to the brain and liver.

The medical team identified the specific genetic variant for KJ's disease shortly after his birth and, within just six months, designed and manufactured a gene-editing therapy to specifically correct his disorder. Now the study's authors hope to replicate the result in other rare diseases: "We want every patient to have the opportunity to live an experience like KJ's, and we hope that other academic researchers will replicate this method for many rare diseases and offer a fair chance at a healthy life to more patients," Musunuru concludes.