Custom Gene Therapy Saves Infant's Life in Breakthrough Six-Month Effort.

At first glance, baby KJ looks like any other healthy, smiling child. But only months ago, he faced life-threatening odds due to a rare and severe metabolic disorder. Thanks to a rapid and unprecedented scientific effort, KJ received a personalized gene therapy tailored specifically to his condition—and he is now thriving.

The innovative treatment, recently documented in the New England Journal of Medicine, represents the first ever on-demand gene therapy designed for an infant with a genetic disorder. This feat was only possible due to seamless collaboration across multiple scientific disciplines and organizations, all working under extraordinary time pressure.

KJ was diagnosed shortly after birth with carbamoyl-phosphate synthetase 1 (CPS1) deficiency, an extremely rare genetic disease affecting just one in 1.3 million people. The disorder impairs the body’s ability to eliminate ammonia, leading to toxic buildup that can cause irreversible brain damage or death in about half of all cases.

Dr. Petros Giannikopoulos, a molecular pathologist at the Innovative Genomics Institute (IGI), explained the critical nature of the enzyme CPS1 in the urea cycle. Without functional CPS1, ammonia clearance fails—creating an urgent need for intervention. At a 2024 meeting of the NIH’s somatic cell gene editing consortium, Giannikopoulos joined forces with geneticist Fyodor Urnov and cardiovascular geneticist Dr. Kiran Musunuru to tackle KJ’s unique case.

Their plan involved using base editing, an advanced form of CRISPR-Cas9 gene editing that avoids breaking the DNA strand. The technique instead swaps out individual bases using bacterial enzymes, allowing for safer and more precise correction of mutations. However, KJ’s specific mutation was previously unknown, demanding a custom-built approach from the ground up.

Time was not on their side. Without swift intervention, KJ’s only other option would have been a liver transplant—a high-risk and uncertain outcome. The team collaborated with physicians at the Children’s Hospital of Philadelphia and industry partners to expedite development.

Luckily, IGI had an existing relationship with the Danaher Corporation, whose subsidiaries—Integrated DNA Technologies, Alvedron, and Acuitas Therapeutics—rallied to supply the necessary materials. These included messenger RNA for the base editor, guide RNA to direct the correction, and a liver-targeting lipid nanoparticle for delivery.

According to Giannikopoulos, the choice to use base editing was driven by both safety and efficiency. Packaging the entire system into one lipid nanoparticle made the method viable within the tight time constraints.

Every potential editing outcome and off-target effect was thoroughly evaluated before moving forward. “We had to consider every angle,” said Giannikopoulos. “There was no room for ego—just the shared goal of saving a child’s life.”

Within six months of their initial discussion, the therapy underwent preclinical animal testing and received an expedited review from the FDA. KJ received his first dose soon after. Because his mutation resulted in a premature stop codon, KJ’s body had never produced CPS1, raising concerns about a possible immune reaction.

Fortunately, close monitoring revealed no signs of inflammation, and KJ responded well. He went on to receive two more escalating doses. Today, as he nears his first birthday, KJ can eat a normal-protein diet and requires fewer medications than other CPS1 patients.

Giannikopoulos, who previously worked in oncology, emphasized that the medical field must reassess its tolerance for risk in treating genetic diseases. “In cancer, we accept high toxicity—even in infants—to achieve remission,” he said. “With genetic diseases, we need to rethink what it means to treat aggressively and effectively.”

Recent FDA guidance has opened the door for "umbrella trials" in gene therapy, allowing slight variations in treatment to be evaluated under a single regulatory framework. This model could speed up the development of personalized treatments like KJ’s for other patients with similar mutations.

For Giannikopoulos and the team, this case signals more than a single success. “To me, this marks the beginning of interventional medical genetics,” he said—where precision tools and collaborative science converge to rewrite the future of rare disease treatment.

Source:https://www.the-scientist.com/understanding-the-nuts-and-bolts-of-qpcr-assay-controls-72292

This is non-financial/medical advice and made using AI so could be wrong.