“Imagine you’re a surgeon, and before surgery, you go for a walk outside, find the sharpest stick on the ground, and say, ‘This is what we’re going to use to take an appendix out.’”
That is how Benjamin Oakes, PhD, described the initial state of CRISPR-based genome engineering when he was not only a University of California Berkeley graduate student in the labs of CRISPR pioneer Jennifer Doudna, PhD, and David F. Savage, PhD, but also as it stands today.
For over a decade, Oakes has been on a mission to develop a suite of genome and epigenome editing tools built for unique molecular advantages in activity, specificity, and deliverability that translate into safer and more effective genetic therapies, which led him to co-found Scribe Therapeutics in 2018 with Doudna, Savage, and Brett Staahl, PhD. This week at the American Heart Association (AHA) Scientific Sessions 2024, Scribe Therapeutics revealed that their genome editing and epigenetic modifying technologies are knocking on the door of clinical trials for major cardiometabolic diseases affecting millions of patients.
Scribe showed that both its CRISPR X-Editor (XE) gene editing technology and Epigenetic Long-Term X-Repressor (ELXR) epigenetic modifying technology, which target proprotein convertase subtilisin/kexin type 9 (PCSK9), can safely and durably reduce low-density lipoprotein cholesterol (LDL-C) levels up to 55% for one year and 67% for nearly six months, respectively, in the livers of non-human primates (NHPs) in vivo. The company also demonstrated highly effective reduction of apolipoprotein C-III (APOC3) and triglyceride levels by more than 90% in vivo with the XE gene editing technology in mice.
“At AHA, we presented data that validate both of these technologies and their potential to empower patients—including millions suffering from cardiometabolic disease—to rewrite their future,” Oakes told Inside Precision Medicine. “Our latest data are proof that the future of medicine is here. The technologies Scribe has developed are opening new doors to safe genetic medicines that will allow physicians, patients, and other drug developers to choose the method best suitable to treat their target disease.”
Not a stick-in-the-mud
Oakes started working on genome-editing proteins when zinc finger nucleases (ZFNs) were the only game in town.
“I cut my teeth on molecular engineering ZFNs, focused on solving the targeting problem,” Oakes told Inside Precision Medicine in early October at the Cell & Gene Meeting on the Mesa in Phoenix, Arizona. “How do I get a ZFN or a zinc finger in general—I built all sorts of different tools with them—to bind a specific site? That took a ton of molecular engineering to get that done right.”
When Doudna and Emmanuelle Charpentier, PhD, solved the genome targeting problem with CRISPRs and guide RNAs (gRNAs), Oakes, like the rest of the world, was stunned. He realized that his molecular engineering approaches could be transferred from ZFNs to CRISPRs, which he did as a graduate researcher at the University of California Berkeley with Doudna and Savage.
“I had a conversation with Dave and Jennifer about what the field of genetic medicine really needs, and what we realized was that most folks, even to this day, are still using essentially the bacterial immune system version of CRISPR—unmodified Cas9—to be a genome editing tool,” said Oakes.
“I don’t want to undersell the power of Cas9 because it is incredibly powerful, but really what we’ve done since is find a molecule that works very well right out of the box—in this case, right out of a microbe that evolved [the molecule] to be a bacterial immune system and it has all of the baggage that comes with that,” Oakes said. “It has baggage in terms of just how potent and specific it can be. It gets the job done, especially in a research setting, but it has not been engineered specifically over time to be a therapeutic. That realization was really the spark… to take [CRISPR] molecules, melt them down, and reforge them into the scalpel that a surgeon actually needs to use.”
About the technology developed at Scribe Therapeutics, Oakes said, “We started with ‘XE’ genome editing. By iteratively engineering this technology from the natural CasX enzyme, we have been able to achieve 100x improvement in activity and no detectable off-target editing—a major improvement from existing CRISPR and Cas9-based technologies. It’s the engineering and data-driven ‘CRISPR by Design’ approach at Scribe’s core.”
The company took a similar approach in developing “ELXR” epigenetic silencing technology, Scribe’s second proprietary platform that harnesses CRISPR in a completely different way from genome editing.
“We have precisely engineered CRISPR-based platforms for editing the genome and modifying the epigenome in ways that are potent, specific, and safe enough to become the standard of care for genetic medicines,” said Oakes.
Transforming standard-of-care
Oakes didn’t decide to take Scribe down the monogenic rare disease route that many gene editing companies have. While these diseases have well-defined genetic causes, they typically have low patient numbers—an issue that has largely kept big pharma from investing in these developmental treatments.
“With cardiovascular disease continuing to top the list of the world’s leading killers and nearly one in 15 adults in the U.S. estimated to suffer from severe dyslipidemia, our industry is behind the curve,” said Oakes. “Furthermore, with more than half of patients not adhering to the current standard of care therapies, it is critical to improve how we can address elevated lipid levels.”
At the AHA 2024 Scientific Sessions, Scribe highlighted work from three programs. Scribe showed new data for STX1150, an engineered CasX-based epigenetic silencer targeting PCSK9 to lower LDL-C levels. This could be used to treat patients with atherosclerotic cardiovascular disease (ASCVD). A single dose of STX1150 demonstrated sustained LDL-C reduction of up to 67% in NHPs for nearly six months and counting.
“The intention with ELXR, and what our data show, is to turn off gene expression of a genetic target by implementing durable epigenetic marks without permanently altering the DNA sequence, making gene expression changes reversible if necessary,” said Oakes. “Even at the therapeutically relevant dose of 0.75 mg/kg, we are able to achieve more than 50% reduction in LDL-C, indicating that ELXR has the potential to be on par with, if not exceed, the standard of care therapies.”
In a parallel approach, Scribe’s CRISPR X-Editor (XE) gene editing technology achieved saturating levels of editing of the PCSK9 locus, resulting in long-term LDL-C reduction of up to 55% for at least a year in non-human primates with no identified off-targets.
Scribe also demonstrated new data for STX1400, a CRISPR XE gene editing therapy that targets the apolipoprotein C-III (APOC3) gene for the treatment of hypertriglyceridemia in familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG) patients. The company demonstrated that STX1400 reduced APOC3 and triglyceride levels by more than 90% in vivo with the XE gene editing technology in mice.
“We believe these preclinical data represent industry-leading approaches demonstrating how engineered CRISPR technologies can uniquely achieve levels of potency and specificity necessary to safely tackle the world’s leading cause of death,” said Oakes. “As Scribe makes further advances to our technology, we intend to lead the broader industry in this direction, ultimately foregoing the need for a pill every day for the rest of one’s life and eliminating risks that are inherent but common to existing genetic therapies. We are committed to continuing to develop these medicines, as well as to building novel genetic medicine approaches for every major cardiometabolic disease. We expect to have further updates to share in 2025.”
