Two weeks ago, scientists at the Children’s Hospital of Philadelphia announced that they successfully used personalized gene editing to treat an infant with a life-threatening, incurable genetic disease. The child was diagnosed with carbamoyl phosphate synthetase 1 (CPS1) deficiency shortly after he was born. 

CPS1 is a urea cycle disorder and, more broadly, an inborn error of metabolism. It occurs when someone carries two defective copies of the CPS1 gene. The CPS1 gene encodes an enzyme, carbamoyl phosphate synthetase I, that controls the first step in the urea cycle.

When the body breaks down proteins in the liver, it generates nitrogen. The urea cycle processes this excess nitrogen, making urea, a chemical that can be excreted by the kidneys. If the CPS1 enzyme fails to function, nitrogen accumulates in the bloodstream in the form of ammonia. Ammonia is toxic, especially to the brain. When excess ammonia is present in the blood, it causes delayed development and intellectual disability as well as other potentially lethal neurological problems.

CPS1 is an autosomal recessive genetic disorder, meaning both parents must carry one defective CPS1 gene (located on chromosome 2) and the child must inherit both defective genes to exhibit the disorder.

Archibald E. Garrod was the first to identify inborn errors of metabolism. He was a British physician-scientist working in the late 19th and early 20th centuries, around the same time Mendel’s work was rediscovered. One of Garrod’s most important scientific contributions was to identify alkaptonuria as an innate, today we would say genetic, disorder. Alkaptonuria is an inborn error of metabolism in which patients lack an enzyme that converts homogentisic acid (HA) to maleylacetoacetic acid (MA).

This all sounds very fancy but is simply another step in breaking down the protein we eat. When all enzymes are functioning properly, this pathway produces carbon dioxide and water which our bodies easily eliminate. When HA is not broken down, our bodies excrete it in urine and when HA is exposed to air, it turns urine black. It was black urine produced by some babies that captured Garrod’s interest. He noted this disorder tended to run in families and was more common in children of first cousin unions. 

A branch of the alkaptonuria pathway is involved in albinism (lack of pigment in skin, eyes, and hair) and phenylketonuria (PKU). In the early 1960s, PKU was one of the first genetic disorders for which a genetic screen, the Guthrie test, was employed.

This remarkable, inexpensive, effective genetic screen prevents serious developmental and intellectual delays in 1/10,000 to 1/15,000 children born in the US each year. The screen involves taking a small sample of blood from an infant using a heel prick. If the baby tests positive for PKU they are put on a diet that severely restricts protein intake. This prevents the build up of a chemical, phenyl pyruvic acid, in the child’s blood that severely damages developing nervous systems.

Unfortunately, CPS1 is more difficult to manage with diet than PKU. Babies, like the child treated with this gene-editing therapy, are kept on a protein-restricted diet and given medications that scavenge excess nitrogen. Typically, this works only partially. infants often need dialysis and/or a liver transplant, both of which still only temporarily address the problem. 

The strategy used in this exciting gene-editing case was based on CRISPR. CRISPR (clustered regularly interspaced short palindromic repeats) is a naturally occurring gene editing system found in some bacteria and used by bacteria to protect themselves from viral infections.

Scientists have engineered CRISPR systems for a wide range of purposes in the laboratory, and now also in the clinic. Because CRISPR uses a guide RNA molecule, it targets specific sequences of DNA. CRISPR’s “magic” is its sequence specificity along with the ability to couple the molecular machinery with enzymes that modify DNA in various ways. 

Shortly after he was born, physicians found that the infant, identified as KJ, carried a specific gene variant of CPS1. Scientists then created a CRISPR-based gene editing therapy that would specifically recognize the variant KJ carried and replace that sequence with the sequence for a functional enzyme. They delivered the gene editing therapy via lipid nanoparticles in late February. Lipid nanoparticles are tiny lipid (fat) spheres that encapsulate and transport drugs, or in this case, the CRISPR gene-editing therapy. Their charge, stability, and composition enable their uptake by cells. Infant KJ received two additional doses in March and April. 

KJ has shown no serious side effects. Additionally, he’s been able to take in more dietary protein, and was able to recover from a cold virus without ammonia building up in his body. Doctors have also been able to reduce his nitrogen scavenger medication. 

Obviously, this experimental treatment is potentially life-changing for KJ, other children like him, and those who love them. But it also serves to pave the way for using CRISPR-based gene editing for other diseases as long as the specific gene variant is known. 

The work that led to KJ’s miraculous treatment began years ago and was funded by the National Institutes of Health (NIH), the target of devastating DOGE/Trump administration cuts. It is just one of so many examples of why funding for scientific research needs to return to and remain a national priority.