Kyle Muldoon tends to go with his gut. When a profound feeling came over him about this foreign concept, known as gene editing, he knew that an answer to a family crisis was in front of him.
Kyle’s son, KJ, was born with a rare genetic disease known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a metabolic disorder caused by the accumulation of toxic levels of ammonia in the blood. KJ was too young and vulnerable to receive a liver transplant—the standard-of-care option for the disease—and with each day that passed, KJ’s risk for neurological damage or death increased. CPS1 is the most severe form of urea cycle disorder with an estimated 50% mortality in early infancy.
Rebecca Ahrens-Nicklas, MD, PhD, a physician-scientist at Children’s Hospital of Philadelphia (CHOP), approached Kyle and his partner, Nicole Muldoon, with a radical idea for something that had never been done before—a personalized CRISPR therapy that could correct KJ’s individual disease-causing mutation.
The proposal to pursue the experimental treatment was primed by her research to develop a gene editing therapy for the classic inborn error of metabolism, phenylketonuria (PKU), an ongoing collaboration with her former MD/PhD classmate, Kiran Musunuru, MD, PhD, cardiologist and professor of translational research at Perelman School of Medicine at the University of Pennsylvania (Penn).
Musunuru presented the work in a plenary session at the American Association for Gene and Cell Therapy (ASGCT) in New Orleans. KJ’s case is detailed in a study published in the New England Journal of Medicine (NEJM) titled, Patient-specific in vivo gene editing to treat a rare genetic disease.
“We need a patient-first approach for any variant in any patient, whomever, wherever they are. Each and every patient deserves a fair shot at this,” said Musunuru as he held the ASGCT crowd captive.
Kiran Musunuru, MD, PhD, delivering his plenary session at ASGCT 2025. [Kevin Davies]
Two years of work had allowed the researchers to achieve successful gene corrections in animal models of PKU. However, creating a safe and effective personalized therapy to dose a small infant would be an entirely different ball game—one that had to be played fast.
After several spirited debates and hard questions to ensure that they understood the proposal from every angle, Kyle and Nicole gave gene editing the green light.
KJ received the first dose of a customized lipid nanoparticle (LNP)-delivered, bespoke base-editing therapy by intravenous infusion between the age of six to seven months. To maximize benefit while optimizing safety, two additional infusions were administered at rising doses at seven and eight months of age. Within seven weeks after infusion day, KJ was able to tolerate increased dietary protein and receive half the starting dose of his nitrogen-scavenger medication.
KJ had become the world’s first patient to be treated with a personalized CRISPR therapy that made a correction directly to the genome.
Before hopping on a press briefing with reporters, Nicole spotted KJ sitting upright by himself in his crib.
“We didn’t know if gross motor function was something that he was going to be able to do,” Nicole said. “Seeing him reach milestones that are important for any infant blows us away even more because we know what was stacked up against him from the very beginning.”
Ahrens-Nicklas emphasizes that it is still early days to determine KJ’s long term outlook, but highlights that he has made slow but steady progress. KJ is “safer than he was before” with the research team having “much more to learn from him.”
“We want each and every patient to have the potential to experience the same results we saw in this first patient,” stated Musunuru. “The promise of gene therapy that we’ve heard about for decades is coming to fruition, and it’s going to utterly transform the way we approach medicine.”
KJ with his family and doctors (Musunuru and Ahrens-Nicklas) post-infusion day. [Children’s Hospital of Philadelphia]
KJ’s story was a collaborative effort between multiple academic and industry partners, including the Innovative Genomics Institute at UC Berkeley, Mass General Brigham Gene and Cell Therapy Institute, Danaher Corporation, and Acuitas Therapeutics.
For severe diseases, such as CPS1 deficiency, early diagnosis is critical. Once KJ’s genetic testing results came back soon after he was born, the team was off to the races.
Musunuru’s research team was able to determine how to correct one of KJ’s genetic changes within a few weeks. (KJ had two truncating CPS1 variants, referred to as Q335X on the paternal allele and E714X, on the maternal allele. He underwent whole-genome sequencing to uncover the mutation).
Danaher-owned companies, Aldevron and Integrated DNA Technologies, manufactured KJ’s personalized therapy, which required a new guide RNA (gRNA) sequence, mRNA-encoded base editor, custom off-target safety services and clinically validated lipid nanoparticle (LNP) formulation, in six months, a speed that was three times faster than the standard timeline for gene-editing drug products. The effort was aligned with the mission of the Danaher-Innovative Genomics Institute (IGI) Beacon for CRISPR Cures program.
Upon submission of the US Food and Drug Administration (FDA) application to treat KJ, approval hit in just one week.
According to Musunuru, the therapy’s cost was “not as expensive as you might think.” While the traditional road to approval for a gene editing treatment requires rigorous studies that take years to complete to demonstrate safety and effectiveness, KJ’s urgent timelines brought costs down to orders of magnitude less than standard drug development.
“We met early on with the FDA, and they were incredibly supportive of our effort,” said Musunuru. “KJ was very sick and there wasn’t time for business as usual. They told us to do as good of a job as we possibly could in our limited time, and they would take it from there. They honored that commitment.”
Alexis Komor, PhD, associate professor of chemistry and biochemistry at the University of California, San Diego (UCSD), affirms that KJ’s case has set a “nice precedent” for developing a personalized treatment for a rare disease in a timeline that is compatible with treating the disease before harmful progression, while still maintaining safety and scientific rigor.
Komor is the scientist who developed the first base editor whilst a postdoc in the lab of David Liu, PhD. She authored an accompanying editorial in NEJM uncovering the science behind the study along with Andrea Gropman, MD, director of neurometabolic translational research at St. Jude Children’s Research Hospital.
When reflecting on the broader impact of single patient cases, Peter Marks, MD, PhD, former director of the Center for Biologics Evaluation and Research (CBER) at the FDA, urges regulatory approaches to leverage the information that is used repeatedly from product to product, while allowing for the required customization, such as guide RNA in the case of CRISPR constructs.
“Facilitating such a process could transform N-of-1 therapy into N-of-many therapies, thus leading to commercial viability of these products for rare diseases—a development that would ultimately benefit many persons with great unmet medical need,” Marks wrote in his NEJM editorial.
During his nine-year tenure as CBER director, Mark was a key ally to the rare disease community and oversaw the approval of 22 gene therapies. His sudden departure from the FDA earlier this Spring has left the cell and gene therapy’s regulatory outlook uncertain.
Fyodor Urnov, PhD, director of technology and translation at the IGI and a co-author of the NEJM study, has been a passionate proponent for building the scientific, manufacturing and regulatory framework to fully realize the potential of CRISPR gene editing.
“CRISPR-Cas deserves a chance to make a major impact in Mendelian disease treatment space—an impact it is currently not making. This is despite the fact that the technology itself is clinic-grade, delivery to cells and organ systems where such disease is prevalent is also clinic-grade, and the complete toolbox of nonclinical derisking exists,” Urnov declared in a 6,000-word editorial in The CRISPR Journal to “give Cas a chance” in late 2024.
KJ will turn ten months old on June 1st. For Kyle, his son’s story has been one of inspiration and fate.
“If you’re going through something of this nature, it’s important to find the tiniest bead of hope and hold onto that as long as you can,” he said. “[Everything] fell into place and has given us this little fighter of a boy.”
*Fyodor Urnov and Alexis Komor will be speakers at GEN’s 2025 virtual event, The State of CRISPR and Genome Editing, streaming on June 11th.
The post ASGCT 2025: World’s First Patient Treated with Personalized CRISPR Therapy appeared first on GEN - Genetic Engineering and Biotechnology News.
Kyle’s son, KJ, was born with a rare genetic disease known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a metabolic disorder caused by the accumulation of toxic levels of ammonia in the blood. KJ was too young and vulnerable to receive a liver transplant—the standard-of-care option for the disease—and with each day that passed, KJ’s risk for neurological damage or death increased. CPS1 is the most severe form of urea cycle disorder with an estimated 50% mortality in early infancy.
Rebecca Ahrens-Nicklas, MD, PhD, a physician-scientist at Children’s Hospital of Philadelphia (CHOP), approached Kyle and his partner, Nicole Muldoon, with a radical idea for something that had never been done before—a personalized CRISPR therapy that could correct KJ’s individual disease-causing mutation.
The proposal to pursue the experimental treatment was primed by her research to develop a gene editing therapy for the classic inborn error of metabolism, phenylketonuria (PKU), an ongoing collaboration with her former MD/PhD classmate, Kiran Musunuru, MD, PhD, cardiologist and professor of translational research at Perelman School of Medicine at the University of Pennsylvania (Penn).
Musunuru presented the work in a plenary session at the American Association for Gene and Cell Therapy (ASGCT) in New Orleans. KJ’s case is detailed in a study published in the New England Journal of Medicine (NEJM) titled, Patient-specific in vivo gene editing to treat a rare genetic disease.
“We need a patient-first approach for any variant in any patient, whomever, wherever they are. Each and every patient deserves a fair shot at this,” said Musunuru as he held the ASGCT crowd captive.
Kiran Musunuru, MD, PhD, delivering his plenary session at ASGCT 2025. [Kevin Davies]
Safer than he was before
Two years of work had allowed the researchers to achieve successful gene corrections in animal models of PKU. However, creating a safe and effective personalized therapy to dose a small infant would be an entirely different ball game—one that had to be played fast.
After several spirited debates and hard questions to ensure that they understood the proposal from every angle, Kyle and Nicole gave gene editing the green light.
KJ received the first dose of a customized lipid nanoparticle (LNP)-delivered, bespoke base-editing therapy by intravenous infusion between the age of six to seven months. To maximize benefit while optimizing safety, two additional infusions were administered at rising doses at seven and eight months of age. Within seven weeks after infusion day, KJ was able to tolerate increased dietary protein and receive half the starting dose of his nitrogen-scavenger medication.
KJ had become the world’s first patient to be treated with a personalized CRISPR therapy that made a correction directly to the genome.
Before hopping on a press briefing with reporters, Nicole spotted KJ sitting upright by himself in his crib.
“We didn’t know if gross motor function was something that he was going to be able to do,” Nicole said. “Seeing him reach milestones that are important for any infant blows us away even more because we know what was stacked up against him from the very beginning.”
Ahrens-Nicklas emphasizes that it is still early days to determine KJ’s long term outlook, but highlights that he has made slow but steady progress. KJ is “safer than he was before” with the research team having “much more to learn from him.”
“We want each and every patient to have the potential to experience the same results we saw in this first patient,” stated Musunuru. “The promise of gene therapy that we’ve heard about for decades is coming to fruition, and it’s going to utterly transform the way we approach medicine.”
KJ with his family and doctors (Musunuru and Ahrens-Nicklas) post-infusion day. [Children’s Hospital of Philadelphia]
Off to the races
KJ’s story was a collaborative effort between multiple academic and industry partners, including the Innovative Genomics Institute at UC Berkeley, Mass General Brigham Gene and Cell Therapy Institute, Danaher Corporation, and Acuitas Therapeutics.
For severe diseases, such as CPS1 deficiency, early diagnosis is critical. Once KJ’s genetic testing results came back soon after he was born, the team was off to the races.
Musunuru’s research team was able to determine how to correct one of KJ’s genetic changes within a few weeks. (KJ had two truncating CPS1 variants, referred to as Q335X on the paternal allele and E714X, on the maternal allele. He underwent whole-genome sequencing to uncover the mutation).
Danaher-owned companies, Aldevron and Integrated DNA Technologies, manufactured KJ’s personalized therapy, which required a new guide RNA (gRNA) sequence, mRNA-encoded base editor, custom off-target safety services and clinically validated lipid nanoparticle (LNP) formulation, in six months, a speed that was three times faster than the standard timeline for gene-editing drug products. The effort was aligned with the mission of the Danaher-Innovative Genomics Institute (IGI) Beacon for CRISPR Cures program.
Upon submission of the US Food and Drug Administration (FDA) application to treat KJ, approval hit in just one week.
According to Musunuru, the therapy’s cost was “not as expensive as you might think.” While the traditional road to approval for a gene editing treatment requires rigorous studies that take years to complete to demonstrate safety and effectiveness, KJ’s urgent timelines brought costs down to orders of magnitude less than standard drug development.
“We met early on with the FDA, and they were incredibly supportive of our effort,” said Musunuru. “KJ was very sick and there wasn’t time for business as usual. They told us to do as good of a job as we possibly could in our limited time, and they would take it from there. They honored that commitment.”
Alexis Komor, PhD, associate professor of chemistry and biochemistry at the University of California, San Diego (UCSD), affirms that KJ’s case has set a “nice precedent” for developing a personalized treatment for a rare disease in a timeline that is compatible with treating the disease before harmful progression, while still maintaining safety and scientific rigor.
Komor is the scientist who developed the first base editor whilst a postdoc in the lab of David Liu, PhD. She authored an accompanying editorial in NEJM uncovering the science behind the study along with Andrea Gropman, MD, director of neurometabolic translational research at St. Jude Children’s Research Hospital.
When reflecting on the broader impact of single patient cases, Peter Marks, MD, PhD, former director of the Center for Biologics Evaluation and Research (CBER) at the FDA, urges regulatory approaches to leverage the information that is used repeatedly from product to product, while allowing for the required customization, such as guide RNA in the case of CRISPR constructs.
“Facilitating such a process could transform N-of-1 therapy into N-of-many therapies, thus leading to commercial viability of these products for rare diseases—a development that would ultimately benefit many persons with great unmet medical need,” Marks wrote in his NEJM editorial.
During his nine-year tenure as CBER director, Mark was a key ally to the rare disease community and oversaw the approval of 22 gene therapies. His sudden departure from the FDA earlier this Spring has left the cell and gene therapy’s regulatory outlook uncertain.
Fyodor Urnov, PhD, director of technology and translation at the IGI and a co-author of the NEJM study, has been a passionate proponent for building the scientific, manufacturing and regulatory framework to fully realize the potential of CRISPR gene editing.
“CRISPR-Cas deserves a chance to make a major impact in Mendelian disease treatment space—an impact it is currently not making. This is despite the fact that the technology itself is clinic-grade, delivery to cells and organ systems where such disease is prevalent is also clinic-grade, and the complete toolbox of nonclinical derisking exists,” Urnov declared in a 6,000-word editorial in The CRISPR Journal to “give Cas a chance” in late 2024.
KJ will turn ten months old on June 1st. For Kyle, his son’s story has been one of inspiration and fate.
“If you’re going through something of this nature, it’s important to find the tiniest bead of hope and hold onto that as long as you can,” he said. “[Everything] fell into place and has given us this little fighter of a boy.”
*Fyodor Urnov and Alexis Komor will be speakers at GEN’s 2025 virtual event, The State of CRISPR and Genome Editing, streaming on June 11th.
The post ASGCT 2025: World’s First Patient Treated with Personalized CRISPR Therapy appeared first on GEN - Genetic Engineering and Biotechnology News.