How the First Customized Gene Therapy Was Created in Six Months

In May, news broke that a 10-month-old baby, KJ Muldoon, was doing well after receiving 3 doses of the world’s first personalized CRISPR base-editing therapy.

Baby KJ had been diagnosed with carbamoyl phosphate synthetase 1 (CPS1) deficiency shortly after his birth in August 2024. In a mere six months, scientists across academia and industry developed and manufactured a novel, custom therapy that will hopefully help KJ avoid a liver transplant long-term. It may also provide a roadmap for transforming CRISPR therapies for other inborn errors of metabolism.

Six months is three times faster than the standard timeline for developing and manufacturing gene-editing drug products. How was this possible?

Bringing together academic research and biotechnology

The therapy administered to KJ came to fruition through a collaboration between academic teams at Children’s Hospital of Philadelphia (CHOP), Penn Medicine, the University of California Berkeley’s Innovative Genomics Institute (IGI) and the teams at Integrated DNA Technologies (IDT), Aldevron and Acuitas Therapeutics.

KJ’s physicians at CHOP diagnosed him with CPS1 deficiency, a type of urea cycle disorder (UCD). It is a rare and potentially fatal genetic condition caused by a complete or partial lack of the carbamoyl phosphate synthetase enzyme, which is involved in the breakdown of ammonia as part of the body’s urea cycle. Consequently, patients with CPS1 can experience toxic levels of ammonia accumulation in the bloodstream, leading to outcomes such as irreversible brain damage, coma or even death.

“There is currently no cure. Standard treatments focus on controlling ammonia through dietary restrictions and medications, but these approaches are often insufficient, particularly in severe neonatal-onset cases,” Mark Wetzel, vice president and general manager, mRNA CDMO Service at Aldevron, and Sandy Ottensmann, vice president and general manager, Gene Writing and Editing, Integrated DNA Technologies (IDT), told Technology Networks. Liver transplantation is the only definitive treatment, but this carries significant risks and is dependent on donor availability.

DNA sequencing revealed that KJ had been born with mutations in both copies of the CPS1 gene, meaning his body could not produce the CPS1 enzyme. For several years, researchers at CHOP and Penn had been exploring how UCDs – often caused by a single base change – could be treated with a custom base editor. In mouse studies, they had reduced the timeline needed to create such a therapy from years to months. Then, in August 2024, KJ’s case came to their attention.  

“They had been waiting for the right opportunity to apply their research,” said Ottensmann.

CRISPR-Cas9 and base editing: What’s the difference?

In CRISPR-Cas9 genome editing, the Cas9 protein is guided to a specific location within the genome by a guide RNA (gRNA). Once it arrives at this destination, a cut is made that creates a double-strand DNA break. Base editing is slightly different. A modified version of the CRISPR enzyme swaps one base (A, T, C, or G) for another, with high precision. Base editors are in development for the treatment of other conditions including heart disease.

“When KJ was diagnosed with CPS1 deficiency, Fyodor Urnov, professor at UC Berkeley and director, Technology and Translation at the IGI, recognized that this could be the moment to act. Fyodor reached out to Sadik Kassim, CTO at Danaher, who helped bring Aldevron and IDT into the effort,” Ottensmann explained.

“This collaboration brought together the best of academic research and biotechnology innovation to achieve something unprecedented,” said Otterman.

Creating a custom base-editor therapy fast

Time was of the essence, so the teams immediately began mapping out the critical path, process and what would be possible. “IDT mobilized its team of 50+ to work alongside our colleagues at Aldevron and Acuitas Therapeutics, as well as the doctors and researchers at CHOP, to develop a clear plan that we would quickly execute against. We all had to challenge one another to take reasonable risks given the shortened timeline, situation and patient in desperate need,” Ottensmann said.

“The therapy works by delivering a CRISPR system via lipid nanoparticles (LNPs) that enter liver cells and target the mutated DNA. The key components are the Cas9 nuclease, which cuts the DNA at the mutation site, and the guide RNA (gRNA), which directs Cas9 to the exact location of the genetic error. Once the DNA is cut, the cell’s natural repair mechanisms fix the break using a supplied template, correcting the faulty gene,” said Wetzel.

"Each company had an important role to play in creating this drug product,” he continued. “Both Aldevron and IDT had flexible, scalable infrastructures in place. Rather than building systems from scratch, our companies were able to leverage existing GMP facilities and established manufacturing platforms, modifying only where needed for this patient-specific application.”

IDT supplied the custom guide RNA – tailored specifically to KJ’s mutation – and off-target safety services using UNCOVERseq and rhAmpSeq to ensure the CRISPR system would not affect unintended parts of the genome. Aldevron made the mRNA-encoded base editor and the LNPs that delivered it by working with Acuitas, which specializes in development of LNP delivery systems for nucleic acid therapeutics. Aldevron also produced the final LNP-encapsulated, customized in vivo base-editing therapy in a significantly compressed timeline.

“This delivery system allowed the therapy to be administered systemically but act specifically in the liver – the organ affected by CPS1 deficiency,” said Ottensmann. “While previous gene therapies have been aimed at broader corrections, this effort was personalized at every level: molecular design, manufacturing and delivery.”

“It’s a compelling example of how collaborative urgency can redefine what’s possible in biotech,” said Wetzel.

A new precedent for what precision medicine can achieve

Though KJ’s health and response to the custom therapy will require close monitoring over the long-term, initial data is promising: by April 2025, KJ had received three doses of therapy without experiencing adverse side effects. He can tolerate an increased amount of dietary protein and has been able to recover from illnesses, including rhinoviru,s without experiencing ammonia buildup.

“We’ve been in the thick of this since KJ was born, and our whole world’s been revolving around this little guy and his stay in the hospital,” said Kyle Muldoon, KJ’s father. “We’re so excited to be able to finally be together at home, so that KJ can be with his siblings and we can finally take a deep breath.”

The developers behind the custom therapy hope other families can experience a similar sense of relief in the future. “This project sets a precedent for what precision medicine can achieve, especially for inborn errors of metabolism,” said Ottensmann.

“What made this effort transformative is not just the gene correction, it’s how it was approached. Every step, from guide RNA design to safety testing and manufacturing, was personalized and accelerated without compromising quality. This creates a model that can be replicated for other single-gene disorders where speed and accuracy are critical,” she continued.

“With additional investment in infrastructure, regulation and data sharing, this framework could dramatically increase access to personalized therapies for a wide range of genetic conditions,” said Wetzel. “We now know we can compress years into months of work to greatly change a patient’s trajectory of life – and this success should absolutely serve as a roadmap for the development of future personalized therapeutics.”