Scientists Race to Deliver Custom Gene Therapies for Incurable Diseases in Weeks—Not Years

Before the age of one, KJ Muldoon had already made medical history. He was the first person to receive a gene editing therapy specifically designed for him. KJ was born with a deadly gene mutation. His body couldn’t remove ammonia, a byproduct of eating protein. The illness eventually leads to serious brain injury. Roughly half of infants with the disease don’t survive, and those who do suffer severe debilitation and often require liver transplants.

The disease stems from a single mutated DNA letter that prevents the body from making a working enzyme. The clock ticking, teams of scientists developed a gene editor to replace the mutated letter with a normal version. Just weeks after three infusions, KJ was tolerating more protein in his diet and meeting developmental milestones.

Gene editors usually require years to test and perfect. KJ’s treatment took only six months.

Now, his doctors are looking to bring the “transformative” technology to others with rare inherited diseases. In an ambitious clinical trial, they will use base editing—an offshoot of CRISPR gene editing—to correct DNA mutations in rare metabolic diseases. After months of negotiation with the FDA, they have streamlined the convoluted and time-consuming process of gene therapy approval, saving precious time that many young patients don’t have.

A trial could start as early as 2026. At least five kids will receive customized gene editors to test each treatment’s safety and efficacy.

More than 30 million people in the US suffer from rare genetic diseases. Most are so unique that drug companies aren’t willing to invest years to develop gene therapies that only benefit a few, leaving these patients in limbo.

If successful, the trial could launch “a future of ‘interventional genetics’ in which such therapies are the standard of care,” wrote Drs. Rebecca Ahrens-Nicklas and Kiran Musunuru at the Children’s Hospital of Philadelphia in a recently published roadmap of the approach.

A Single Miracle

KJ’s mutation was in the CPS1 gene. A single swapped DNA letter shuts down the liver’s ability to make an enzyme that rids the body of ammonia. Symptoms include vomiting, lethargy, and brain damage. The condition is called urea cycle disorder, or UCD.

Scientists have long known about UCD. While there is a drug to manage symptoms, patients must adhere to a very low protein diet, which limits a baby’s normal development. Viral infections, common in young infants, can also spike ammonia to dangerous levels.

Before treatment, KJ was sequestered in a hospital room, unable to go home and meet his siblings. His symptoms were so severe that at one point his physician discussed palliative care with his heartbroken parents.

Mutations in seven known genes can cause UCD, making a one-size-fits-all gene therapy impossible. But doctors already knew KJ’s mutation—a single letter swap—making him a perfect candidate for base editing.

A version of CRISPR gene editing, base editing is especially good at swapping single DNA letters. Flipping one DNA letter out of the roughly three billion in the human genome seems inconsequential, but the change often alters the final form and function of a protein. In KJ’s case, it saved his life.

Base editing is already in clinical trials for people genetically prone to dangerously high cholesterol levels, with promising initial results. One trial is being led by Verve Therapeutics, which Musunuru co-founded. Other studies are using the tool to correct genetic faults in stem cells that lead to sickle cell disease.

These attempts all target a known mutation in a disease-causing gene shared by people with the same illness. KJ’s genetic typo was unique to him. Any life-saving base editor had to be made from scratch.

Over the next six months, a remarkable collaboration between doctors, academics, and biotech companies crafted KJ’s treatment. Base editors require two components: A guide RNA “bloodhound” that scans the genome for the defect and a protein that swaps out the faulty DNA letter. The team wrapped instructions for both inside tiny bubbles of fat, which once injected, made their way to the liver, the target organ for the therapy.

Within weeks KJ started feeling better. By roughly 10 months of age, he was discharged from the hospital and is now learning to take his firsts steps at home.

The treatment was tailored to KJ, but base editing is plug-and-play. Guide RNA can easily be reprogrammed to hunt down other single-letter DNA mutations that lead to rare diseases. At least in theory. The cost of development can be prohibitive, partly because of the time it takes to test each individual treatment. Regulatory hurdles further draw out the process.

One for All

KJ’s doctors are now pushing for an even faster timeline to treat kids with his condition.

In their proposed trial, five kids with genetic mutations across seven genes will receive a custom treatment similar to KJ’s. The only difference between the treatments will be the guide RNA, which will be tailored to each child’s particular mutation. Doctors will then follow the children’s health for 15 years.

The FDA usually requires safety data for each new gene therapy formulation. Here, however, they agreed on a single safety trial that covers all formulations based on the same principle. KJ’s safety data will also be taken into consideration. This “regulatory innovation” could massively accelerate development time, wrote the team.

KJ’s success story has brought others on board. In July, the Center for Pediatric CRISPR Cures launched at the University of California, Berkeley to pursue technologies for life-saving custom gene therapies in children.

Meanwhile, the Advanced Research Projects Agency for Health, a US government agency, launched two new programs in mid-September to make custom gene therapies for people with rare genetic disorders a reality.

One of these, called THRIVE, is focused on building a platform to rapidly develop personalized gene editing tools. Another, GIVE, aims to bring high-quality cell and gene therapy manufacturing technologies to local clinics, slashing transportation costs. Both initiatives are now welcoming proposals.

“Our vision is to rapidly produce multiple kinds of genetic medicines so that breakthrough treatments are accessible, affordable, and ready to dose within a week of diagnosis,” GIVE program manager Dr. John Schiel said a press release.

Ahrens-Nicklas and Musunuru are confident personalized gene therapy can play a role in future healthcare. “With full-throated support from funding bodies…and from regulatory agencies such as the FDA, we are optimistic that in the coming years, our team and other teams will be able to take tangible steps toward making interventional genetics the standard of care for many diseases,” they wrote.