Scribe Therapeutics Reports Preclinical Data at ASGCT 2026 Demonstrating Enhanced Potency and Specificity of Engineered CRISPR Technologies for Epigenetic Silencing and Gene Editing
Scribe Therapeutics, Inc. a biotechnology company engineering purpose-built CRISPR technologies to reshape the treatment of disease by enabling earlier intervention, improved outcomes, and longer, healthier lives, presented preclinical data on the latest advances across the company’s engineered CRISPR technologies at the 29th American Society of Gene & Cell Therapy (ASGCT) Annual Meeting.
The oral presentations showcased Scribe’s CRISPR by DesignTM approach in engineering naturally occurring CRISPR systems into highly potent and highly specific platforms for genetic medicine, namely Epigenetic Long-Term X-Repressor (ELXR) and X-Editor (XE). ELXR underpins STX-1150, the company’s lead LDL-C lowering program, while XE underpins additional cardiometabolic programs STX-1200, designed for Lp(a) lowering, and STX-1400 for triglyceride lowering.
These data continue to demonstrate Scribe’s engineering capabilities for improving potency, precision, and targetability of CRISPR-based medicines,” said Benjamin Oakes, Ph.D., co-founder and CEO of Scribe Therapeutics. “Engineering epigenetic silencers and genome editors for therapeutic application has resulted in technologies that aim to improve dosing, specificity, and scalability, facilitating durable CRISPR medicines for broad cardiometabolic patient populations. These findings provide important preclinical support as we continue to advance our lead assets, including STX-1150, into the clinic.”
Allosteric CRISPR-Based Epigenetic Silencer for Potent, Precise, and Durable Gene Silencing
In an oral presentation, Scribe reported preclinical data featuring its ELXR technology, a next-generation CRISPR-based epigenetic silencing approach designed to deliver potent, durable gene repression with improved specificity. ELXRs are engineered to enable long-term target gene silencing through epigenetic mechanisms without introducing permanent DNA alterations.
The presentation highlighted an ELXR design that incorporates an allosteric regulatory domain intended to recapitulate DNMT3A’s native autoinhibitory mechanism, providing an additional specificity control to help restrain DNA methyltransferase activity while preserving or improving on-target silencing. The result is a highly specific epigenetic editor that remains “locked”, i.e., preventing unwanted off-target activity, until the molecule encounters a “key” also written at the on-target site, creating a mechanism akin to two-factor authentication.
In preclinical studies, allosteric ELXRs demonstrated enhanced potency and specificity across multiple targets, including sustained in vivo knockdown of PCSK9 with an improved transcriptional specificity profile. These data support the development of Scribe’s ELXR technology and its application in STX-1150, the company’s lead pipeline program advancing towards clinical development.
Additional highlights from the presentation include:
- Engineering increased on-target repression across multiple targets, averaging at least 4-fold improvement in activity across spacers in vitro. Allosteric ELXRs also improved performance of lower-activity guide RNAs, suggesting potential utility in expanding guide options for target gene silencing
- Allosteric ELXRs showed improved specificity readouts, reducing off-target transcriptional effects by approximately 10-to-100-fold compared to non-allosteric molecules
Engineering X-Editor Technology for Therapeutic-Grade In Vivo Genome Editing
In a second oral presentation, Scribe reported on its XE technology and featured DeepXE, an AI-enabled predictive model designed to accelerate identification of potent guide RNAs for XE-based therapeutics.
The presentation demonstrated how Scribe has engineered XE with substantially improved activity and specificity from naturally occurring CRISPR-CasX through large-scale protein and guide RNA engineering. Furthermore, Scribe emphasized its ability to engineer XE for effective editing of specific, high-priority genomic sites with a desired therapeutic mechanism of action. By applying mechanistic insight into how sequence and genomic context impact editing activity, Scribe fine-tunes its screening platforms to enable the development of novel enzymes with potent and precise targeting of disease-relevant sites.
DeepXE further supports and accelerates this engineering strategy by enabling prediction of guide RNA potency and reducing the need for empirical screening, helping to identify guide RNAs with high on-target activity for therapeutic targets more rapidly. Together, these findings show how Scribe integrates protein and guide engineering with predictive modeling to support the development of XE-based therapeutic programs.
Additional highlights from the presentation include:
- Preclinical in vivo data showed potent, saturating liver editing across multiple target loci in non-human primates, and specificity studies in primary human hepatocytes showed no significant detectable off-target editing for multiple therapeutic guides at a super-saturating dose of 10X EC90
- DeepXE is designed to accelerate guide selection by reducing screening burden by 50% with less than a 10% false-negative rate, and enable faster optimization of XE-based therapeutics
Translating CRISPR by DesignTM into Scribe’s Lead LDL-C Lowering Program
In a third invited oral presentation, Scribe described how its CRISPR by DesignTM engineering approach integrates engineering of both the CRISPR foundational molecule, XE, and the key epigenetic silencing components, including novel repressor and allosteric regulatory domains, to create the ELXR technology underlying STX-1150. The presentation emphasized how engineering advances used to transform naturally occurring CRISPR-CasX into XE also underpin ELXR performance, including improved guide RNA binding, RNP formation, target search kinetics, genomic targetability, potency, and specificity.
By combining this engineered CasX-derived foundation with optimized epigenetic silencing components, Scribe developed ELXR molecules designed to achieve potent and durable silencing of target genes without permanent DNA alterations. These learnings were applied to STX-1150, with preclinical prototype data showing durable PCSK9 repression following single-dose LNP delivery and specific target repression in transcriptome-wide specificity studies, with sustained epigenetic silencing activity that translated into durable LDL-C lowering observed in non-human primates for nearly 18 months and ongoing.
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