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Baby KJ is the first person in the world to undergo personalized gene therapy using base editing technology <\/p>\n
(Photo: Children’s Hospital of Philadelphia)<\/p>\n
KJ, the fourth child of Kyle and Nicole Muldoon, was born a few weeks early in Pennsylvania and initially appeared healthy. However, shortly after birth, he began showing symptoms that led doctors to suspect meningitis or sepsis \u2014 a severe and life-threatening response to a blood infection. Thanks to the vigilance of his caregivers, dangerously high levels of ammonia were detected in his blood, and the doctors quickly realized that his critical condition was not caused by an infection.<\/p>\n
The infant was transferred to the Children\u2019s Hospital of Philadelphia (CHOP), where the medical team began treatment to remove the excess ammonia from his body. At the hospital, KJ\u2019s genome was sequenced, revealing a defect in both copies of the gene responsible for producing the CPS1 enzyme. This meant his body could not produce the enzyme, which plays a crucial role in the urea cycle \u2014 the body’s process of eliminating ammonia, a toxic byproduct of protein breakdown, by converting it into urea.<\/p>\n
In healthy individuals, ammonia is converted into urea in the liver, enters the bloodstream and is then filtered by the kidneys and excreted in the urine. But for those lacking a functioning CPS1 enzyme, ammonia accumulates in the body to toxic levels. This condition is life-threatening because ammonia is especially harmful to nerve cells and can cause brain damage, coma and death. It is also an extremely rare condition, affecting only one in every 1.3 million newborns.<\/p>\n
Treatment for CPS1 deficiency typically involves reducing protein intake in the patient\u2019s diet and administering medications that help eliminate ammonia \u2014 until the child is old enough for a liver transplant with a functioning urea cycle. However, during this time, spikes in ammonia levels \u2014 such as those triggered by infections \u2014 can lead to irreversible brain damage or death.<\/p>\n
\u201cWhen we Googled CPS1 deficiency, we saw there were two likely outcomes \u2013 a liver transplant or death,\u201d said Nicole, KJ\u2019s mother. \u201cWe were in shock.\u201d Faced with this devastating reality, she and her partner decided to keep KJ hospitalized for as long as necessary, so he could receive round-the-clock care to maximize his chances of survival. Due to his critical condition, KJ was placed on the liver transplant waiting list at just five months old \u2014 a transplant that might arrive too late.<\/p>\n<\/p>\n
Meanwhile, KJ\u2019s medical team began working on a potential treatment that might be able to repair one of the defective copies of his gene in the liver. Rebecca Ahrens-Nicklas, a physician and researcher at the Children\u2019s Hospital of Philadelphia, and Kiran Musunuru, a doctor and geneticist at the University of Pennsylvania, along with their colleagues, described the race to develop the gene therapy in a paper published in the New England Journal of Medicine.<\/p>\n
Ahrens-Nicklas and Musunuru have been collaborating for several years in an effort to find ways to correct genetic errors \u2014 mutations \u2014 in the livers of children suffering from urea cycle disorders. Their focus was on base editing, a CRISPR-based gene-editing enables the alteration of a single base, or \u201cletter\u201d, in DNA. The CRISPR system, which scientists began using only in the past decade, has revolutionized genetic engineering. It enables easy and rapid gene editing and is often described as “genetic scissors” that cut both strands of the DNA. In contrast, base editing is more like using an eraser and pencil \u2014 it makes a small nick in one DNA strand, enabling the replacement of a single base.<\/p>\n
To help children born with urea cycle disorders, mutations must be corrected as early as possible, before irreversible damage occurs. To that end, Ahrens-Nicklas and Musunuru developed a workflow to accelerate the production of a personalized base-editing system from the moment a patient\u2019s disease-causing mutation is identified. The researchers had practiced the process, selecting a known genetic error that causes a urea cycle disorder and working as fast as possible to develop a suitable editor. In each trial, they managed to reduce the time required to find a solution \u2014 from over a year to just a few months.<\/p>\n
KJ\u2019s mutation was the seventh they attempted to rapidly correct \u2014 but this time, it wasn\u2019t just a lab exercise. This time, it was a real, sick baby.<\/p>\n
Ahrens-Nicklas, Musunuru and their team \u2014 in collaboration with researchers from the Innovative Genomics Institute (IGI) at the University of California, Berkeley, several biotechnology companies and with federal funding from the U.S. National Institutes of Health (NIH) \u2014 developed a gene therapy for KJ in record time. They worked almost nonstop, including through holidays. By the time KJ was one month old, the researchers had already grown cell cultures carrying his specific mutation to test the treatment. A month later, they had a working base-editing system.<\/p>\n
<\/p>\n 4 View gallery <\/p>\n CRISPR <\/p>\n (Illustration: Shutterstock)<\/p>\n The system is encased in a tiny fatty bubble (lipid nanoparticle) that protects it and helps it enter liver cells. Inside the bubble are the instructions for producing the editor, along with a small genetic sequence (gRNA) that guides the editor precisely to the location where the incorrect letter in one copy of KJ\u2019s gene needs to be corrected. This sequence was named \u201ckayjayguran\u201d after the baby.<\/p>\n COVID-19 vaccines use similar lipid bubbles, though they don\u2019t carry instructions to alter genetic sequences. Instead, they temporarily instruct cells at the injection site to produce a specific viral protein.<\/p>\n Five months after KJ\u2019s birth, the completed gene therapy \u2014 named \u201ck-abe\u201d \u2014 was tested on cell cultures and genetically engineered mice carrying the defective gene. The treatment successfully corrected the mutation. However, as it often happens with the CRISPR system, it also caused some unintended changes in other regions of the DNA. Fortunately, testing showed that these off-target genetic changes did not cause harm. It is similar in a way to correcting a typo in the sentence \u201cCats have many supestitions,\u201d so it reads \u201cKats have many superstitions\u201d after the correction. The change outside the word \u201csuperstitions\u201d doesn\u2019t alter the meaning of the sentence and, therefore, is harmless.<\/p>\n At the same time, the researchers were also testing the therapy\u2019s safety in a macaque monkey. When KJ was six months old, the researchers submitted the test results and an application to the U.S. Food and Drug Administration (FDA) for approval of the therapy as an investigational new drug for a single patient. The FDA approved the request within a week, and several biotech companies collaborated to produce the treatment at cost and at a quality suitable for human use.<\/p>\n Once the researchers knew they had an approved treatment, Ahrens-Nicklas finally told KJ\u2019s parents that she might have good news. \u201cMy biggest fear in all of this was giving false hope to a family,\u201d she said.<\/p>\n![\"\u05e2\u05e8\u05d9\u05db\u05ea](\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/05\/Syc2Oz511ll_0_0_3000_1800_0_x-large.jpg\" "\\"CRISPR")
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