June 3, 2025

Infant with rare disease receives customized gene therapy

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Drs. Kiran Musunuru (left) and Rebecca Ahrens-Nicklas with the infant patient who received personalized gene therapy for a rare and life-threatening genetic disorder.  

Children's Hospital of Philadelphia

More than 30 million Americans have some type of rare disease. Most are caused by an abnormality in just one gene. In recent years, different forms of gene therapy have been developed and FDA-approved to correct or replace faulty genes and treat conditions like sickle cell disease, various blood disorders, and a severe skin condition. But developing such approaches for treating unique or ultrarare conditions has been challenging and can be costly.

A team of researchers at the Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania set out to develop a way to create personalized gene therapy for patients with rare metabolic disorders. Led by Drs. Rebecca Ahrens-Nicklas and Kiran Musunuru, the scientists focused on inherited conditions that lead to toxic buildup of ammonia in blood and tissues, called urea cycle disorders. These conditions arise from faulty liver enzymes that can’t convert ammonia to urea.

The researchers had spent years developing and testing potential gene-editing therapies for these disorders in animal and cellular models. So they were prepared when a newborn patient displayed potential symptoms of a very rare type of disorder called carbamoyl-phosphate synthetase 1 (CPS1) deficiency. People with this condition can’t process byproducts from protein metabolism in the liver, which leads to ammonia buildup. The excess ammonia can severely damage the brain and liver. Standard treatment for CPS1 deficiency includes a low-protein diet until the child is old enough for a liver transplant. But the children are at risk for organ failure during this waiting period. About half of infants diagnosed with CPS1 deficiency die in early infancy.

With support from NIH, the scientists quickly took steps to gain FDA approval for their experimental gene therapy, which they customized to correct the infant’s particular mutation. The therapy used an advanced gene-editing technology called CRISPR base editing to precisely edit and correct the rare mutation in this child’s CPS1 gene. The gene-editing molecules were encased in fatty nanoparticles and infused into the liver. This was the first known case of a personalized gene-editing medicine being given to just one person. The approval process took only six months, from diagnosis to the start of gene therapy. Results were described in the New England Journal of Medicine on May 15, 2025. 

At first, the child received a very low-dose infusion of the experimental therapy at six months of age. A higher dose was then given three weeks later.

Within weeks after the infusions, the patient was able to receive a greater amount of dietary protein and needed less medication to keep ammonia levels in check. No serious side effects were observed. The child was also able to recover from a cold without ammonia buildup in his body. Such common childhood illnesses can be extremely dangerous for patients with CPS1 deficiency.

The researchers note the need for long-term follow-up to fully test the safety and effectiveness of this therapy. But with further study, this type of personalized gene therapy holds promise for treating a variety of disorders.

“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible,” says Ahrens-Nicklas. “And while he is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs.”

Related Links

• Genome Editing Restores Hearing in Mice
• Developing Treatments for Prion Diseases
• Learning To Control Microglia Using CRISPR
• Carbamoyl Phosphate Synthetase I Deficiency Disease
• About Inborn Errors of Metabolism
• What Is Genome Editing?

References

Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. Musunuru K, Grandinette SA, Wang X, Hudson TR, Briseno K, Berry AM, Hacker JL, Hsu A, Silverstein RA, Hille LT, Ogul AN, Robinson-Garvin NA, Small JC, McCague S, Burke SM, Wright CM, Bick S, Indurthi V, Sharma S, Jepperson M, Vakulskas CA, Collingwood M, Keogh K, Jacobi A, Sturgeon M, Brommel C, Schmaljohn E, Kurgan G, Osborne T, Zhang H, Kinney K, Rettig G, Barbosa CJ, Semple SC, Tam YK, Lutz C, George LA, Kleinstiver BP, Liu DR, Ng K, Kassim SH, Giannikopoulos P, Alameh MG, Urnov FD, Ahrens-Nicklas RC. N Engl J Med. 2025 May 15. doi: 10.1056/NEJMoa2504747. Online ahead of print. PMID: 40373211.

Funding

NIH’s National Center for Advancing Translational Sciences (NCATS), National Institute of Neurological Disorders and Stroke (NINDS), Office of the Director (OD) Office of Strategic Coordination’s Somatic Cell Genome Editing Program, National Cancer Institute (NCI), and National Heart, Lung, and Blood Institute (NHLBI); Acuitas Therapeutics; Integrated DNA Technologies; Aldevron; Danaher; Children’s Hospital of Philadelphia Research Institute.