When Mass General Brigham researchers shared their unpublished enzymes, they helped physician-scientists at CHOP create a treatment for a baby with a rare genetic disease.
From left: Rachel Silverstein and Ben Kleinstiver
Researchers know that a small act of generosity can have a big ripple effect. It’s why sharing resources—such as a newly designed enzyme for gene editing—isn’t all that uncommon.
But when Benjamin Kleinstiver, PhD, and his team decided to share their unpublished enzymes with colleagues at Children’s Hospital of Philadelphia (CHOP), it helped spark something truly special.
In mid-May, CHOP revealed that they had successfully used those enzymes as part of a gene therapy to treat a baby who had been born with a rare genetic disease known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a condition that causes ammonia to build up in the blood. The baby, KJ, received his first dose of a bespoke therapy in February of 2025, and he is now thriving.
The bespoke (custom-made) therapy that KJ received is the culmination of collaborations that span hospitals, health systems, and industry partners, with everyone contributing expertise to help ensure that new therapies can reach the people who need them most.
While Kleinstiver is quick to point out that his group’s contributions of sharing their unpublished enzymes with the CHOP team was a small act, it was nonetheless a significant one, leading to a treatment for KJ and a milestone for gene therapy.
“This treatment and the improvement in KJ’s health is a big ‘win’ for science and genetic therapies in general,” said Kleinstiver, an investigator in the Center for Genomic Medicine at Massachusetts General Hospital.
“We hope it is just the beginning and that soon, this model can be used to create bespoke enzymes that can be utilized in customized treatments for patients with a range of other diseases.”
Behind the Scenes of a Bespoke Therapy
Kleinstiver, who is also a Kayden-Lambert MGH Research Scholar 2023-2028, has made significant contributions to the field of gene editing over the years. His lab optimizes CRISPR-Cas9 proteins and combines them with a type of enzyme called “base editors” that can make single letter changes to the genome.
This kind of precise editing is needed to treat many human diseases, such as the single letter mutation that caused KJ’s condition.
Kleinstiver's team has recently developed new approaches to improve the properties of CRISPR-Cas9 enzymes, including a machine learning-based method to predict efficient and safe enzymes that can precisely edit disease-causing sequences.
Their findings and methodology were published in late April in Nature (read more here). But before their publication, they had an opportunity to make a difference for a patient.
A Race to Treat Baby KJ
Logan Hille
KJ was born in August of 2024, and received a diagnosis of CPS1 deficiency shortly after birth. But not long after that, researchers across the country were banding together to try to help him.
Kiran Musunuru, MD, PhD, MPH, a physician-scientist at CHOP and former postdoctoral fellow at MGH, contacted colleagues, looking for the most promising enzymes to help deliver gene therapy for KJ. When Musunuru contacted the Kleinstiver lab, whose group is known for tweaking CRISPR-Cas proteins, they immediately offered their assistance.
“We were happy to share our unpublished enzymes with Kiran’s group, given the potential advantages of these new technologies in terms of efficiency, safety, and precision,” said Kleinstiver.
Rachel Silverstein, PhD, a graduate student in the Kleinstiver lab (and first author of the Nature paper) helped design the specific enzyme that was utilized in KJ’s therapy. Working together with Silverstein, Logan Hille, PhD, also designed a few additional enzymes for Musunuru’s lab to test.
The focus of both Rachel and Hille’s PhD studies were to take different approaches to engineer precise, effective, and safe CRISPR-Cas9 enzymes that could one day be utilized in genetic therapies – unbeknownst to them, that day came much sooner than they had imagined.
“It’s remarkable that Rachel published her paper in Nature and contributed to an enzyme design that helped treat a patient, all before she even defended her PhD,” said Kleinstiver. Silverstein successfully defended her PhD on April 28—less than three months after KJ received his treatment.
Kleinstiver’s group sent several newly developed and unpublished enzymes to Musunuru’s team, which they then tested in cell models to decide which enzyme was the safest and most effective to treat their patient.
They found that the enzymes generated using the MGH team’s machine learning algorithm—known as PAMmla—proved to be superior and used them for KJ’s treatment.
Researchers hope that KJ’s experience will be the first but far from the last successful treatment with a personalized CRISPR gene editing therapy.
“This work shows that base editing can be highly effective to treat metabolic disease, and that the process from genetic diagnosis to treatment can be relatively quick when there’s great alignment in expertise and motivation to save lives,” said Kleinstiver.
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