SEVILLE – The annual conference of the European Society of Gene & Cell Therapy (ESGCT) arrived in the capital of Andalusia this week. The undoubted highlight of the opening plenary session was an update on one of the biggest gene therapy stories of 2025.
Kiran Musunuru, MD, PhD (Perelman School of Medicine at the University of Pennsylvania) followed up his plenary at the American Society of Gene & Cell Therapy five months ago with a recap of the groundbreaking partnership that successfully treated infant KJ Muldoon, affectionately known as “Baby KJ.”
Musunuru provided thousands of ESGCT delegates with promising news of a roadmap to build on the lessons learned over the past 12 months following the diagnosis and treatment of Baby KJ in a milestone for the development of N-of-1 gene editing therapies.
Musunuru opened his plenary talk by noting that his medical interests span a vast distance —from the rarest of rare diseases to cardiovascular disease, the leading cause of death worldwide, claiming 18 million lives each year. In 2014, Musunuru’s lab was the first group to permanently suppress PCSK9 as a potential therapeutic approach for cardiovascular disease using CRISPR-Cas9. That approach has been commercially developed and refined by Verve Therapeutics, a company Musunuru co-founded with Sek Kathiresan, MD, and was acquired by Lilly last July.
In 2021, Musunuru teamed up with Rebecca Ahrens-Niklas, MD, PhD (Children’s Hospital of Philadelphia, CHOP) to study patients with neonatal errors of metabolism, specifically patients with hereditary urea cycle disorders that cause the build-up of toxic levels of ammonia. With many patients having rare, private mutations, Musunuru said, “We’d have to personalize the therapies to a degree that had never been done before.”
The need for early intervention is intense. Infant mortality rates are higher than 50%. Even if the infant survives, surges of ammonia can result in brain injury. A liver transplant must be held off until 12 months of age and is accompanied by a high risk of morbidity and mortality, trading one chronic condition for another.
Meeting the challenge
It took “a few years to meet these challenges,” Musunuru said, but the Philadelphia team got its chance last year.
Baby KJ was born with a rare recessive disorder, a deficiency of a liver enzyme called CPS1, resulting in dangerously high levels of ammonia some 30X higher than normal. The baby had “the most severe form of the most severe disorder” in the urea cycle category, Musunuru said. He was originally admitted to CHOP to wait for a liver transplant, not to become the guinea pig for a bespoke base editing treatment.
As was well documented back in May, Musunuru and Ahrens-Niklas identified the specific CPS1 mutations in Baby KJ and went to work. They used lentivirus-transduced cell lines to test the relative editing efficiency of different constructs. “It was all about speed, we couldn’t let perfect be the enemy of the good,” Musunuru said.
The best guide RNA, with a relaxed PAM preference, was identified within four weeks of KJ’s birth. Colleagues in Boston—Ben Kleinstiver, PhD (Mass General Hospital) and David Liu, PhD (Broad Institute)—helped improve the efficiency and specificity of the adenine base editor two weeks later. Together with Fyodor Urnov, PhD (Innovative Genomics Institute) and colleagues, Musunuru and Ahrens-Niklas forged an impressive public-private partnership, including scientists and resources from Aldevron, IDT, Acuitas Therapeutics, and The Jackson Laboratory.
Four months after KJ’s birth, Musunuru’s team held a pre-IND (investigational new drug) meeting with officials at the U.S. Food and Drug Administration (FDA). “They were incredibly supportive of our effort and committed to a rapid review,” Musunuru said. Meanwhile, colleagues at IDT, Aldevron, and elsewhere completed toxicology and dosing studies by around the five-month mark. Clinical production of the reagents was completed by the six-month anniversary of KJ’s birth.
Two weeks later, Musunuru’s team performed extensive off-target analysis using three orthogonal techniques, using KJ’s own genome sequence (and that of his father). The results showed low-level bystander editing at the wild-type CPS1 allele (as expected) and minimal off-target editing deep within an intron of a copper transporter gene, which was not deemed relevant to KJ’s condition. The results of additional off-target studies were also sent to the FDA.
At this point, Musunuru and Ahrens-Niklas submitted their single-patient IND to the FDA, which was approved in just seven days.
KJ received the first dose of his lipid nanoparticle/custom base editor at age seven months, with escalating doses following 22 days and 62 days later. Other than some mild coughing and a low-dose fever, he experienced no ill effects. A very promising sign, Musunuru said, is that KJ has grown from the 9th percentile to the 40th percentile after his third dose. Tests demonstrate that he has a partially functional urea cycle.
“I avoid using the world cure,” Musunuru cautioned. “We have a responsibility not to exaggerate and give undue hope to the families.” He said KJ essentially has a milder form of his disease. Indeed, he is healthy enough now that it would be unwarranted to do a liver biopsy.
Patient to platform
The KJ story was not a clinical trial, but a shining example of providing clinical care. “We need to move from N-of-1 studies to platform trials,” Musunuru said.
Musunuru and his colleagues are now designing a master protocol for a primary IND clinical trial that would encompass patients with seven urea cycle disorders, including OTC deficiency, arginase deficiency, and citrullinemia type I. The protocol would include gene-specific INDs but allow for amendments to be made with in vitro data supplied for each variant-specific guide RNA. After treating five patients, Musunuru said his team could discuss with the FDA the move to a Phase III trial.
Musunuru closed his speech by thanking KJ’s parents and displaying a “before and after” photograph of the little boy upon admission to CHOP and at ten months of age—“graduation day”—shortly before he received a police escort home and a wave of national TV appearances.
ESGCT 2025: Seville, Spain, October 7-10, 2025.
The post Baby Steps: Kiran Musunuru Lays Out the Path Beyond KJ at ESGCT appeared first on GEN – Genetic Engineering and Biotechnology News.
