Gene Editing at Scale, Clinic Seeks Generalizable Therapies

Ajay Gannerkote, president of Integrated DNA Technologies (IDT), says what’s most exciting about CRISPR is its potential to shift medicine from managing disease to directly correcting its root cause. “For patients with severe genetic conditions, especially those with no existing treatment options, that represents a fundamental change in what’s possible,” he said.

IDT played a pivotal role in manufacturing the personalized gene editing therapy given to baby KJ Muldoon to treat his rare metabolic disorder. Today, KJ is free from the toxic ammonia buildup that drives a 50% mortality rate for his condition in infancy. While his story highlights the life-changing potential of gene editing, the field now wrestles with the next challenge: expanding these therapies to benefit broader patient populations.

In contrast to KJ’s urea cycle disorder, which stemmed from a single disease-causing mutation that could be precisely targeted, many genetic disorders arise from numerous mutations scattered across a gene where individualized corrections are too resource-intensive to scale.

Gannerkote says turning powerful gene editing tools into broadly accessible clinical therapies requires progress across multiple fronts. Many CRISPR therapies are still bespoke, with manufacturing processes that are not yet standardized or easily repeatable, leading to long timelines and high costs. In regulation, therapy developers and government regulators face a learning curve when evaluating new modalities, particularly when speed is critical for patients with life-threatening conditions.

Today’s gene editing companies reflect on what’s required to scale personalized CRISPR therapies for maximized impact in the clinic.

End-to-end

Sadik Kassim, PhD, CTO of Genomic Medicines at Danaher, explains that personalized therapies do not naturally lend themselves to traditional drug-development models. Gene editing companies are now seeking “platformization,” where common manufacturing processes are standardized, and limited elements, such as guide RNAs, are customized for each patient to reduce costs and speed timelines.

“Baby KJ’s treatment succeeded because multiple elements aligned simultaneously,” explained Kassim. The foundational science, which achieved successful gene corrections in animal models of phenylketonuria (PKU), an inherited metabolic disorder caused by mutations in the PAH gene that impair the enzyme responsible for breaking down phenylalanine, had already been developed in the academic labs led by Children’s Hospital of Philadelphia (CHOP) physician scientists, Rebecca Ahrens-Nicklas, MD, PhD, and Kiran Musunuru, MD, PhD. Teams were then able to move quickly when the clinical need became clear.

Regulatory engagement was also critical. Danaher teams worked directly with the FDA to streamline the treatment approval process without compromising patient safety. That collaboration compressed a timeline that would normally take 18–24 months down to roughly six months.

“Replicating this for future patients will require moving away from one‑off efforts and toward repeatable platforms with established processes, validated assays, and clearer regulatory precedents, so that speed becomes the norm rather than the exception,” Kassim said.

Amy Pooler, PhD, CSO of ElevateBio, agrees that the transition steps between therapy design and manufacturing are often where the greatest delays occur. ElevateBio seeks to address this bottleneck by building an end-to-end genetic medicine platform.

“A critical driver for the company is making sure we have a clear line of sight into manufacturing from the very beginning,” Pooler said. “One reason Baby KJ’s case was successful is that Danaher managed the handoffs smoothly.”

Pooler also describes developing genetic medicines as “building the plane while you’re flying it.” The field still lacks enough data to reliably predict patient outcomes. Every clinical trial readout provides a valuable lesson for the field.

“I’m excited about the clinical evidence that’s starting to accumulate, showing gene editing can be transformative for patients, which we didn’t have five to ten years ago,” she said.

Large gene, generalizable therapy

ElevateBio’s expanding CRISPR toolbox includes base, prime, and epigenetic editing. Notably, the Durham-based company’s AI platform generates novel recombinases for targeted gene insertion, an approach that holds promise as a generalizable medicine that could treat patients regardless of their underlying disease-causing mutation.

Using AI-guided design, ElevateBio explores entirely new regions of protein space to discover potent and highly specific recombinases that expand the range of diseases amenable to gene editing. These engineered enzymes, which possess 50% or less homology to known proteins, can access novel genomic regions that remain difficult to target with existing CRISPR technologies.

Ben Kleinstiver, PhD, associate investigator at Massachusetts General Hospital (MGH) and co-author of the NEJM study describing KJ’s case, says the FDA’s Plausible Mechanisms Pathway has helped address some of the regulatory challenges to streamline the path to the clinic. Yet, there remains a major motivation for pan-mutation approaches that are more widely applied across patients.

Kleinstiver’s research group, in collaboration with Full Circles Therapeutics, recently developed a circular single-stranded DNA donor (ssDNA) that enables safer kilobase-scale integration for human cells.¹ The technology provides an alternative to double-stranded DNA (dsDNA) donors that evoke harmful immune responses yet are required for recognition by the diverse suite of genome editing enzymes. Notably, the new circular donor maintains recombinase compatibility by attaching a short region of dsDNA that can go undetected by the cytosolic DNA sensor and immune system activator, cGAS.

Patients now

While the gene editing field often concentrates on large indications driven by a single common mutation, Edward Kaye, MD, CEO and director of Aurora Therapeutics, aims to extend these technologies beyond the “lucky few” who share the same mutation.

Co-founded by Jennifer Doudna, PhD, CRISPR Nobel Laureate, and Fyodor Urnov, PhD, scientific director of the Innovative Genomics Institute, Aurora launched in January to build a sustainable pipeline to scale rare disease treatments. Traditionally, developing therapies for these ultra-rare or N-of-1 conditions can require several million dollars for a single patient.

Aurora is pursuing an “umbrella IND” strategy that allows multiple guide RNAs to be evaluated within a single clinical trial. The company’s initial focus is on PKU.

PKU offers several advantages for early clinical development. Patients are routinely identified through newborn screening programs shortly after birth, which facilitates trial participant identification and enrollment. The condition also benefits from a clear regulatory precedent: reductions in phenylalanine levels are an established clinical endpoint used to move therapies toward approval.

“What we learn from PKU will be used for many other diseases because we have the systems in place,” said Kaye. “It expands gene editing into many more patients, by going after one disease first.”

Kaye also stresses the importance of engaging patient communities, whose input can ensure studies and regulatory processes are not overly burdensome for patients and families.

Maher Masoud, CEO of MaxCyte, emphasizes putting patients at the forefront. He adds that most gene-editing therapies in the clinic require significant patient conditioning, which can lead to lengthy treatment cycles and clinical trial timelines. Yet he sees these barriers to scale being eroded over the near term. As an example, modalities, such as allogeneic cell therapies, require far less patient conditioning and easier dosing regimens to support cheaper therapies.

In 2013, MaxCyte partnered with CRISPR Therapeutics on early work that led to the first FDA-approved therapy based on CRISPR-Cas9, Casgevy, with MaxCyte’s ExPERT electroporation platform enabling the efficient delivery of gene editing machinery into cells.

More than a decade later, the company has developed more than 1,000 applications and protocols. The broad engineering platform can repeatedly engineer batches of at least 20 billion cells using CRISPR-Cas9 in addition to base and prime editing.

Masoud says low-significant gene editing commercial success has been a bottleneck to scaling personalized therapies. Yet, he reiterates that CRISPR and other gene editing technologies were discovered a short 12 years ago.

“With CRISPR, we are finally seeing cures, Casgevy, LYFGENIA, and baby KJ are proof of that,” he says. “This is just the beginning.”

References

1. Tou, C.J., Xie, K., Ferreira da Silva, J., et al. Invasive DNA donors and recombinases license kilobase-scale writing. Nature. 2026. DOI: 10.1038/s41586-026-10241-z.

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