For the first time, doctors have treated a baby born with a rare, life-threatening genetic disorder with a gene-editing therapy scientists tailored to specifically repair his unique mutation. The baby boy, born with a devastating genetic disease, is thriving after becoming the first known person to receive a bespoke, CRISPR therapy-for-one, designed to correct his specific disease-causing mutation.
The baby received three infusions containing billions of microscopic gene-editors that homed in on a mutation in his liver and appear to have corrected his defect. Doctors need to follow the boy longer to determine how well the treatment is working. But so far, the therapy appears to have at least partially reversed his condition, reducing his risk of suffering brain damage and possibly even death.
The ‘miracle’ recovery of the baby boy was recently published in the
New England Journal of Medicine (NEJM), and neurologist Timothy Yu of Boston Children’s Hospital, who leads a collaborative of teams developing personalized treatments for rare genetic disorders, quoted, “It’s a heroic effort and a really nice proof of principle.”
The boy, first treated in February at just 7 months old, still needs a special diet and medication; the experimental therapy alone isn’t enough to prevent a dangerous buildup of ammonia in his blood caused by a faulty gene for a key liver enzyme.
Still, the swift development of a gene editor that appears to have repaired the defect in some of his liver cells is a landmark demonstration of a personalized approach that has tantalized rare disease researchers.
What is CRISPR?
CRISPR is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea. Each sequence within an individual prokaryotic CRISPR is derived from a DNA fragment of a bacteriophage that had previously infected the prokaryote or one of its ancestors.
CRISPR gene editing is a genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. It is based on a simplified version of the bacterial CRISPR-Cas9 antiviral defense system.
Dr. Timothy Yu’s treatment relies on a base editor, a variation on CRISPR.
With CRISPR, an enzyme fully cuts DNA at a specific site in the genome determined by a strand of guide RNA. In base editors, CRISPR’s enzyme is altered so it only nicks one of DNA’s double strands. A second enzyme then swaps out a DNA base, correcting a single “letter” misspelling. Base editors infused into the body to edit liver cells have shown success at treating adults with a high cholesterol disease and another genetic disorder.
The path to ‘miracle’:
Cardiologist Kiran Musunuru and physician-scientist Rebecca Ahrens-Nicklas, both from the University of Pennsylvania, wanted to tackle a bigger challenge after developing a treatment for metabolic diseases. They aimed to create base editors, which are tools that can fix gene mutations in young patients with urea cycle disorders. These disorders occur when genes that help the liver convert ammonia into urea are faulty. When ammonia builds up in the blood, it can lead to serious health issues like lethargy, coma, or brain damage.
The team's goal was to quickly find the best combination of base-editing tools to repair mutated genes in these patients. They first tested their methods on mice with a condition called phenylketonuria. By making their process faster, they reduced the time to design a custom base editor from 1-2 years to just a few months and successfully cured the mice.
The perfect patient:
In August 2024, they found a baby, nicknamed KJ, who had a severe urea cycle disorder. KJ was diagnosed with carbamoyl phosphate synthetase 1 (CPS1) deficiency, which occurs in about 1 in 1 million births. Doctors managed KJ's ammonia levels with a special diet and medication, but he might still need a liver transplant.
The team worked quickly to create a base editor to treat KJ's condition within 6 months. After testing in animals, they received approval to use lipid nanoparticles containing the editing tools in a nearly 7-month-old baby (in February 2025).
Although they couldn't do a liver biopsy to confirm the treatment's success, indirect signs show it was effective. After receiving three doses, KJ can eat more protein and needs less medication to lower his blood ammonia levels. He also experienced two viral infections without the usual ammonia crisis.
KJ's treatment allowed for only three doses, and he is not fully cured yet. However, his doctors are hopeful that he can avoid a liver transplant. As he grows, he may receive more doses. KJ is reaching his developmental milestones, and his father expressed happiness with the results. He will be able to go home from the hospital soon.
The treatment did cause some liver enzymes to rise, indicating an immune response to the nanoparticles, but these levels returned to normal quickly. Like CRISPR, base editors can change unintended DNA sequences, and tests showed a minor off-target change that is not expected to cause harm. Ahrens-Nicklas expressed excitement about the safety of the treatment and its potential benefits for KJ. Musunuru hopes this approach could help many others worldwide.
More on the treatment:
This base editor treatment builds on previous efforts that started 7 years ago with a tailored RNA drug used to help a girl with a severe neurological disorder. While that method primarily targets neurological issues, base editors seem promising for liver diseases, as the liver effectively absorbs the nanoparticles carrying the editing tools.
Another promising method uses a CRISPR-like tool to insert a functioning gene into the genome instead of fixing a broken one. A baby who received this treatment for a different urea cycle disorder, ornithine transcarbamylase (OTC), was reported in January to be off all special diets and medication.
However, this gene insertion method uses a virus, which carries its own risks. Currently, this treatment can only be given once and is more expensive to produce than base editors. Medical geneticist Cary Harding supports exploring different strategies to treat these rare but serious conditions. He emphasizes that all these approaches are still experimental and deserve investigation.
One step to a healthier you—join Times Health+ Yoga and feel the change
Start a Conversation
Post comment