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Guidance opens doors for rare disease treatments, but academic teams will likely need industry partners to meet rigor required for FDA approval PHILADELPHIA, March 31, 2026 /PRNewswire/ -- Researchers from Children's Hospital of Philadelphia (CHOP) and Penn Medicine, along with collaborating institutions, reported results today supporting a customizable in vivo prime editing platform designed to treat infantile-onset urea cycle disorders (UCDs), rare liver diseases that can cause dangerous ammonia buildup, and other liver-centered genetic diseases. The work was reported today in The American Journal of Human Genetics. Continue Reading Rebecca Ahrens-Nicklas, MD, PhD, and Kiran Musunuru, MD, PhD, MPH, ML, MRA In February 2026, Rebecca Ahrens-Nicklas, MD, PhD, Director of CHOP's Gene Therapy for Inherited Metabolic Disorders Frontier Program and Kiran Musunuru, MD, PhD, MPH, ML, MRA, Co-Director of the Orphan Disease Center, a partnership between CHOP and Penn Medicine, celebrated the one‑year anniversary of baby KJ Muldoon, an infant born with severe CPS1 deficiency, becoming the world's first person to receive a personalized gene‑editing therapy – an initiative they led. That same week, Ahrens-Nicklas and Musunuru were on hand when the U.S. Food and Drug Administration (FDA) announced its draft "plausible mechanism" framework for faster development of highly personalized genetic treatment. Following up on their previous work with the FDA on UCDs, Ahrens-Nicklas and Musunuru, along with their collaborators at the Broad Institute, tested a flexible gene‑editing method called prime editing that can be quickly adapted to correct genetic variants causing seven urea cycle disorders. They conducted this research specifically with the plausible mechanism framework in mind. The team built a two-part prime editing system: a lipid nanoparticle (LNP) that delivers mRNA encoding the editor to the liver, plus a customized adeno-associated virus (AAV) that supplies the short guide RNAs. In liver cell models, the researchers screened many editing solutions and identified a solution that efficiently corrected a harmful genetic variant present in UCD patients in numerous countries around the world. In preclinical studies, giving the AAV first and the LNP two weeks later corrected about 30 to 40% of the copies of the genetic variant in the liver DNA – much higher than the roughly 10% correction researchers typically consider necessary for a clinical benefit for UCDs. "This two‑part approach delivers robust, potentially therapeutic, correction in liver tissue and has the potential to be rapidly customized for individual patient genetic variants," said Ahrens‑Nicklas. "We see a clear path to move personalized therapies for ultra‑rare liver diseases into practice if we apply late‑stage rigor early on in safety, manufacturing, and quality controls." The researchers recently had a meeting with the FDA to discuss a single "umbrella‑of‑umbrellas" phase I/II trial, under the plausible mechanism framework, that would allow patients across all seven UCD genes to enroll while receiving customized prime-editing therapies. "We view the FDA's draft plausible mechanism framework guidance as an opportunity to accelerate development and approval of individualized therapies for ultra‑rare genetic diseases," said Musunuru. "At this time, it appears that a shortened approval pathway, relying on a single clinical trial, would require sponsors early on to meet the same rigorous standards normally expected in late‑stage development. Academic teams aiming to take individualized therapies through to FDA approval will likely need close partnerships with industry to succeed in this space." The work was supported by the NIH Common Fund Program, Somatic Cell Genome Editing (SCGE) program grants U19-NS132301 and U01-TR005355. The research team has made related Pre-IND briefing materials and the FDA's written responses available via the SCGE Translational Coordination and Dissemination Center; a link to the additional information is included in the peer-reviewed manuscript. Feierman et al. "Implications of the FDA's New Plausible Mechanism Framework for the Development of a Personalized In Vivo Prime Editing Platform." Am. J. Hum. Genet. Online March 31, 2026. DOI: 10.1016/j.ajhg.2026.03.018. About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Ashley Moore Children's Hospital of Philadelphia (267) 426-6067 [email protected] SOURCE Children's Hospital of Philadelphia 21% more press release views with Request a Demo