FDA Framework Spurs Personalized Gene Editing for Rare Liver Diseases

Researchers develop customizable in vivo prime editing platform to treat urea cycle disorders

Mar. 31, 2026 at 3:30pm

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A highly textured, abstract painting in soft greens, browns, and blues, featuring sweeping geometric shapes and precise botanical spirals, conceptually representing the complex genetic and biological forces involved in treating rare liver disorders.Researchers develop a customizable gene-editing platform to treat rare liver diseases, leveraging the FDA's new framework for faster approval of personalized therapies.Philadelphia Today

Researchers from Children's Hospital of Philadelphia (CHOP) and Penn Medicine have reported results 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. The work was done with the FDA's new 'plausible mechanism' framework in mind, which aims to accelerate development and approval of individualized therapies for ultra-rare genetic diseases.

Why it matters

The FDA's new framework opens the door for faster development of highly personalized genetic treatments for rare diseases, but academic teams will likely need industry partnerships to meet the rigorous standards required for approval. This research demonstrates a potential path forward for bringing individualized therapies to patients with ultra-rare liver conditions.

The details

The researchers 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, they screened many editing solutions and identified one that efficiently corrected a harmful genetic variant present in UCD patients globally. 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 typically considered necessary for a clinical benefit for UCDs.

  • In February 2026, the researchers celebrated the one-year anniversary of baby KJ Muldoon becoming the world's first person to receive a personalized gene-editing therapy.
  • That same week, the FDA announced its draft 'plausible mechanism' framework for faster development of highly personalized genetic treatments.

The players

Rebecca Ahrens-Nicklas

Director of CHOP's Gene Therapy for Inherited Metabolic Disorders Frontier Program.

Kiran Musunuru

Co-Director of the Orphan Disease Center, a partnership between CHOP and Penn Medicine.

Children's Hospital of Philadelphia (CHOP)

A non-profit, charitable organization founded in 1855 as the nation's first pediatric hospital, known for its commitment to patient care, training, and research.

Penn Medicine

A health system that partners with CHOP on the Orphan Disease Center.

Broad Institute

A research collaboration that worked with the CHOP and Penn Medicine team on this project.

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What they’re saying

“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.”

— Rebecca Ahrens-Nicklas, Director of CHOP's Gene Therapy for Inherited Metabolic Disorders Frontier Program

“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.”

— Kiran Musunuru, Co-Director of the Orphan Disease Center

What’s next

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.

The takeaway

This research demonstrates how the FDA's new 'plausible mechanism' framework can help accelerate the development of highly personalized genetic treatments for ultra-rare diseases, but academic teams will likely need close partnerships with industry to successfully navigate the rigorous standards required for approval.