Philly scientists helped shape proposed FDA guidance that could accelerate gene therapies for rare diseases

Newly proposed federal guidelines could enable more treatments like the first-of-its-kind gene therapy developed last year for a Philadelphia-area infant with a rare disease.

The custom drug fixed the genetic mutation driving KJ Muldoon’s rare metabolic disease, dramatically improving his liver function.

The draft guidance released late last month by the Food and Drug Administration reflects a central tension: What made KJ’s treatment so groundbreaking also exposed gaps in the existing regulatory framework.

The therapy was custom-made for KJ’s genetic mutation, meaning it would not necessarily work for every baby with the same disease. Many rare diseases are caused by multiple genetic mutations that can differ from patient to patient.

Under the current regulatory system, scientists would need to conduct a clinical trial and seek approval for every version of the therapy they develop. That would be expensive, laborious, and effectively impossible for diseases with hundreds of possible mutations.

“Of course, no one’s going to do it,” said Penn Medicine’s Kiran Musunuru, who developed KJ’s treatment with Children’s Hospital of Philadelphia’s Rebecca Ahrens-Nicklas.

Both worked closely with federal regulators on the draft guidance that enables scientists to instead test the underlying platform against a sample of mutations. If approved, they could then customize the platform for individual patients without conducting an entirely new clinical trial each time.

Musunuru called the approach “a huge boon” for the gene-editing field, which has been advancing toward personalized therapies for ultrarare diseases.

» READ MORE: Feds award $43 million to Philly gene therapy research to advance treatments for rare diseases

A trio comprising Musunuru, Ahrens-Nicklas, and CHOP doctor Lindsey George received a $39 million federal award last summer to develop a scalable platform for treating rare genetic, liver-related diseases in infants and children.

“It’s what will make it feasible to bring this technology forward for patients,” said George, who develops gene therapies for bleeding disorders.

Musunuru and Ahrens-Nicklas first approached the Food and Drug Administration in February 2024 to discuss the need for a new approach to regulation.

They were working on gene-editing medicines for a rare disease called phenylketonuria (PKU), where the body is unable to break down the amino acid phenylalanine. Over time, the inherited disorder can cause severe brain damage.

The current practice is to restrict patients to a low-protein diet, usually encompassing medical food, starting from birth. They may also need daily pills and injections for life.

Musunuru, who had been working on a gene-editing treatment for cholesterol, proposed using that same drug platform to correct the genetic mutations behind PKU, creating a more permanent fix.

Think of the gene as a string of letters, and the mutation as a single-letter typo. His goal was to correct that misspelling.

Some misspellings occur more commonly than others. Take PKU: The most frequent mutation affects around a third of patients in the U.S.

Musunuru and Ahrens-Nicklas developed several versions of a gene-editing drug, each targeting different mutations behind PKU to cover a wider swath of patients.

“They’re the same drug basically,” Musunuru said.

“You just change the GPS,” he added, comparing the drug’s search-and-find function to a navigation system.

Eager to start testing the treatment in a clinical trial, the scientists asked the FDA in early 2024 if they could simply do a single clinical trial for the different versions of the drug, rather than having to do separate trials for each.

FDA officials said they weren’t sure, Musunuru recalled.

“This was probably the first time or one of the first times they were asked this kind of question,” he said.

That inspired a series of meetings where they discussed what a clinical trial and manufacturing of the drug would look like.

By the summer of 2025, Musunuru and Ahrens-Nicklas once again asked the FDA if they could treat their therapy as six different versions of the same drug, rather than as six different drugs.

They said yes.

The scientists were able to work out a new framework called “an umbrella clinical trial,” Musunuru said, where different versions of a gene-editing drug could be treated under the same trial.

This framework was the premise behind draft guidance the FDA released in February to enable clinical trials for individualized ultrarare disease treatments.

Last month’s proposed guidance takes the concept a step further by defining the approval process.

Instead of each version of a drug needing separate approval, all variations of the gene-editing therapy would have the same name on the drug label.

“This is exactly what we were hoping to see and what we’ve been talking about with the FDA,” Musunuru said.

George, who has traveled to the nation’s capital three times in the past 15 months to discuss personalized gene-editing therapies with the FDA, concurred.

The FDA outlined a new term called “the individualized feature space,” which essentially refers to the accepted variation between versions of a drug.

If a new version is within those parameters and has the same core features, it doesn’t need to be tested in a whole new clinical trial. That makes it possible to customize the drug for new patients after approval, even if their mutations weren’t included in the clinical trial.

George hopes the agency will eventually provide more details about requirements for “postmarketing surveillance,” the monitoring of a drug’s long-term effects and safety after approval.

She emphasized that scientists still need to complete the clinical trials to show that their personalized gene-editing medicines are safe and effective.

“We have our work cut out for us,” she said.

The Massachusetts-based company Beam Therapeutics is now setting up a clinical trial for Musunuru and Ahrens-Nicklas’ PKU gene-editing medicine.

The draft guidance would make it easier to attract companies to invest in personalized gene therapies for rare diseases, Musunuru said, by making it more economically feasible to test and seek approval for the medicines.

“Companies should be doing this with rare diseases, but they haven’t wanted to because they haven’t perceived there to be a return on investment,” he said.

The FDA is currently accepting comments regarding the draft guidance, which has not been finalized, until Nov. 27.