A breakthrough for baby KJ

Baby KJ Muldoon is alive today because of a historic breakthrough in customized gene therapy. Having exhausted conventional treatments, doctors recommended putting KJ on comfort care. His parents told The New York Times, “We loved him, and we didn’t want him to be suffering.” Children born with such rare diseases often have little hope of survival.

KJ’s disease is very rare—affecting only between 1 in 800,000 and 1 in 1,300,000 children. He was born with severe carbamoyl-phosphate synthetase 1 (CPS1) deficiency. Without functional CPS1, ammonia accumulates to rapidly toxic levels in the bloodstream, which may lead to a coma or death. Half of all babies with the disorder die within their first week of life.

Using a gene-editing technique known as CRISPR (an acronym for clustered regularly interspaced short palindromic repeats) a team at Children’s Hospital of Philadelphia and Penn Medicine determined to take a new path to treating KJ.

Now 9 ½ months old, what makes KJ’s case so monumental is that he is the first patient of any age to have received a customized gene-editing treatment designed precisely for his genetic mutation. This is the first of what researchers hope will be a new way of treating certain genetic disorders.

Dr. Kiran Musunuru and his colleagues published the results of their innovative treatment in the May 15 issue of The New England Journal of Medicine and also announced it at the annual meeting of the American Society of Gene & Cell Therapy. Getting permission to use a treatment that’s never been used on a particular condition is not easy. But because KJ’s condition was so dire, it was approved by the appropriate regulatory groups, including the FDA.

The good news is that KJ’s condition was based in a single gene. The bad news was that it can occur in different genes in different patients, and because so few children had the disease, there was little to no clinical history to work from. A therapy so individualized and so unique would usually take many years and be very costly to develop.

Once Musunuru and his team got approval, they gave KJ his first customized gene-based infusion. They waited to see if his condition would improve. There was only minor and temporary improvement. Twenty-two days later, they tried again. KJ’s treatment was made more difficult by the fact that he had two viral infections and the complications that go along with that, vomiting and diarrhea. Nevertheless, they began to see improvement over time.

Little KJ is not out of the woods yet. Time will tell. His condition will be closely monitored with lab work, regular liver biopsies, and there is still a potential liver transplantation in store. But the early signs are promising.

Treatments of a single patient with a rare or ultrarare disorder are called N-of-1 therapies. In an editorial in The New England Journal of Medicine, Dr. Peter Marks says that there are more than 7,000 rare diseases affecting about 30 million people in the United States and 300 million worldwide. Although not all rare diseases may end up being treatable, this breakthrough could mean that thousands to hundreds of thousands might be helped.

There is good reason to think that with the appropriate funding of experimental research and efficient regulatory approval processes, increasing numbers of personalized N-of-1 therapies will be possible. But just because we can do something, doesn’t necessarily mean we should.

Jennifer A. Doudna and Emmanuelle Charpentier received a Nobel Prize in Chemistry in 2020 for developing the CRISPR-Cas9 method of gene editing. The technology is revolutionary, being widely developed, and contributing to new therapies that make the dream of curing inherited diseases a reality in some cases.

The same technology may one day also be used to modify genes for selecting traits in so-called designer babies. Parents may be able to choose from a menu of desirable traits for their children like high-IQ, athletic ability, or other enhancements. Careful ethical deliberation and oversight must occur alongside the technological developments.

In addition, CRISPR might be used to modify germ cells (reproductive cells) that would be passed from one generation to another. Nearly seven years ago, Chinese scientist He Jiankui became a scientific pariah for using CRISPR to modify the germline of twin embryos without appropriate ethical guidelines, including doing it in secret.

Germline modification is ethically fraught in part because scientists lack the tools necessary for understanding the risks germline editing might involve. Human germline modification is currently banned in over 70 countries, including the United States, Europe, and China. Editing the human germline raises fundamental questions about the dignity and integrity of every human life. The challenge ahead is to keep the human being first and not to let the technology be the driver.

Meanwhile, everyone is rooting for Baby KJ!