Scribe Therapeutics Highlights Major ASCVD Lipid Insights at AHA 2025
Scribe Therapeutics Inc. (“Scribe”), a leading genetic medicines company engineering next-generation in vivo CRISPR-based treatments, unveiled a series of breakthrough preclinical findings across its cardiometabolic pipeline at the 2025 American Heart Association (AHA) Scientific Sessions. The company’s latest data, which span three key investigational programs—STX-1150 for LDL-C reduction, STX-1200 for lowering lipoprotein(a), and STX-1400 for triglyceride reduction—underscore Scribe’s Therapeutics strategy to deliver durable, highly specific, and potentially transformative one-time therapies for addressing major drivers of atherosclerotic cardiovascular disease (ASCVD).
Scribe’s platform is built around its proprietary suite of engineered CRISPR technologies, including the compact and high-fidelity CasX/CasXE systems. These novel editors are designed to overcome the limitations of earlier Cas9-based approaches, both in terms of specificity and suitability for scalable, safe in vivo applications. At AHA 2025, the company provided compelling evidence that its engineered CRISPR architectures can offer unprecedented durability and potency, while avoiding permanent genome modifications in some applications. This combination of features positions Scribe’s Therapeutics medicines to potentially serve as long-term or even one-time treatments for some of the most prevalent and high-risk lipid disorders.
Aarif Khakoo, M.D., M.B.A., Chief Scientific Officer and Head of R&D at ScribeTherapeutics, emphasized the urgent need for therapies that can bridge the persistent real-world gap between clinical efficacy and long-term patient adherence. “In cardiovascular care, the gap between efficacy in a controlled clinical trial setting and adherence-adjusted outcomes from real-world evidence keeps patients from reaching treatment goals and avoiding preventable cardiovascular events,” he said. He noted that many lipid disorders require chronic, lifelong therapies—yet most patients struggle with adherence, leading to sub-optimal outcomes. Scribe’s genetic medicines, he explained, are engineered to deliver long-term control of lipid drivers at a low dose, with exceptional specificity, enabling a shift from chronic disease management toward durable prevention.
Benjamin L. Oakes, Ph.D., co-founder and CEO of ScribeTherapeutics, echoed this sentiment, noting that the data unveiled at AHA represent a marked advancement in the field of CRISPR medicines. “These results demonstrate that comprehensive engineering of CRISPR technologies can produce medicines with markedly improved safety and performance, surpassing the limitations of early Cas9-based systems,” Oakes said.
He underscored that the ultimate promise of gene-targeted medicines is to provide protection similar to that seen in people born with beneficial genetic variants—individuals who naturally have lifelong low LDL-C levels, low triglycerides, or minimal lipoprotein(a). “We are approaching a pivotal moment in creating therapies that can mirror the durable protection conferred by beneficial human genetics found only in the lucky few,” he said. “Our mission is to democratize these insights into standard-of-care medicines that shift the paradigm of cardiovascular care for all.”
STX-1150: A CRISPR-Based Epigenetic Silencer Delivering >515 Days of Durable LDL-C Lowering Without Genome Modification
One of the most significant data packages presented by Scribe Therapeutics focused on STX-1150, a next-generation CRISPR-based epigenetic silencer delivered via lipid nanoparticles (LNPs). STX-1150 leverages a CRISPR-CasX-derived system to repress PCSK9 mRNA expression without making permanent edits to the genome. This RNA-level repression approach mirrors validated modalities such as siRNA but is engineered for substantially enhanced durability and precision.
PCSK9 is a well-established regulator of LDL receptor recycling. Lowering circulating PCSK9 leads to increased LDL receptor levels and more efficient clearance of LDL-C from the bloodstream. While several PCSK9-targeting therapies exist—including monoclonal antibodies and siRNAs—these treatments require frequent or semi-regular dosing and depend heavily on patient adherence. STX-1150 aims to overcome this challenge by providing long-term, adherence-independent LDL-C lowering through a single treatment.
Key Findings from the AHA 2025 Presentation
- Exceptional durability:
A single dose of the STX-1150 prototype at a therapeutically relevant 0.75 mg/kg achieved ≥50% LDL-C lowering for more than 515 days in non-human primates (NHPs). This represents one of the longest durations of LDL-C suppression demonstrated for a gene-targeted therapy without permanent genomic changes. - Strong lipid-lowering efficacy:
Across multiple dose levels, STX-1150 produced up to:- 90% reductions in circulating PCSK9, and
- 68% reductions in LDL-C,
demonstrating both potency and dose responsiveness.
- Favorable safety profile:
Treated NHPs showed no elevations in liver enzymes relative to controls. Additionally, transcriptome-wide assays in human primary hepatocytes revealed no meaningful off-target gene expression changes, highlighting the precision of the epigenetic silencing platform.
Taken together, these findings support STX-1150 as a potentially first-in-class, durable epigenetic medicine that could offer a long-term alternative to chronic lipid-lowering therapies. The data also reinforce Scribe’s Therapeutics broader platform strategy—using CRISPR-based epigenetic modulation to achieve therapeutic goals without permanent DNA alteration.
STX-1200: A First-in-Class CRISPR Therapy Achieving >95% Lp(a) Reduction at Sub-0.5 mg/kg Doses
Scribe Therapeutics also presented compelling preclinical results for STX-1200, a CasXE-based gene-editing therapy designed to inactivate LPA, the gene encoding apolipoprotein(a), the key component of lipoprotein(a) [Lp(a)]. Elevated Lp(a) is one of the strongest independent hereditary risk factors for ASCVD, affecting nearly 20% of the global population. Despite its impact, there are no approved therapies that can durably and directly reduce Lp(a) levels.
STX-1200 is engineered to provide a one-time, long-lasting solution by making a precise, permanent edit that disables production of the LPA protein.
Key Data Highlights
- Highly potent Lp(a) reduction:
In a transgenic mouse model expressing human LPA, a single dose below 0.5 mg/kg achieved more than 95% reduction in Lp(a)—a dramatic level of lowering with major therapeutic implications. - Exceptional specificity:
Off-target analysis across more than 100 nominated genomic sites in primary human hepatocytes revealed no detectable off-target editing, even at a 10x EC90 supersaturating dose. This level of fidelity is critical for enabling a safe, one-time editing approach in large, genetically defined patient populations. - Potential global impact:
Given the high prevalence of elevated Lp(a) and its strong causal role in ASCVD, STX-1200 has the potential to become a landmark therapy capable of addressing a major unmet need for millions of patients who currently have no effective treatment options.
As the first CRISPR-based therapy to demonstrate meaningful Lp(a) lowering in vivo at low doses, STX-1200 highlights the transformative potential of Scribe’s Therapeutics engineered CasXE system.
STX-1400: Achieving First- and Best-in-Class Saturated Editing of APOC3 (>75% of the Liver) in Primates
The third major data set focused on STX-1400, an LNP-delivered CasXE editor targeting APOC3, a gene encoding apolipoprotein C-III. APOC3 plays a critical role in regulating triglyceride-rich lipoproteins, and loss-of-function variants are associated with dramatically reduced triglyceride levels and lower coronary disease risk. By inactivating APOC3, STX-1400 aims to address severe hypertriglyceridemia (SHTG), familial chylomicronemia syndrome (FCS), and broader triglyceride-driven cardiovascular disease.
Key Findings from the AHA 2025 Presentation
- Groundbreaking hepatic editing:
The STX-1400 surrogate molecule achieved >75% editing of the APOC3 locus in the livers of NHPs at a 1.0 mg/kg dose. This represents the first demonstration of saturated APOC3 editing in primates at a pharmacologically relevant dose. - Dramatic triglyceride lowering:
In hypertriglyceridemic mouse models, STX-1400 reduced:- APOC3 expression by more than 95%, and
- triglyceride levels by more than 95%,
showing powerful mechanistic alignment with the genetic underpinnings of triglyceride metabolism.
- High specificity and safety:
Off-target studies in human primary hepatocytes revealed no detectable editing across over 200 nominated off-target sites, even at doses 10 times higher than required for therapeutic effect.
These results indicate that STX-1400 may hold first-in-class potential to deliver a durable, genetically precise therapy for patients with severe triglyceride disorders who currently experience inadequate treatment options or significant disease burden.
A New Era of CRISPR-Based Cardiometabolic Medicine
Across all three programs—STX-1150, STX-1200, and STX-1400—Scribe Therapeutics has demonstrated the power of its engineered CRISPR platform to deliver highly potent, durable, and specific in vivo edits or epigenetic modulations. Together, these results point toward a fundamentally new approach to treating cardiometabolic diseases: one where a single treatment could provide years of benefit or even lifelong protection, independent of patient adherence.
The company’s data at AHA 2025 reinforce not only the promise of its individual programs but also the broader potential of its engineered CRISPR toolkit to move beyond the limitations of early gene-editing technologies and redefine the possibilities of genetic medicine.
About Scribe Therapeutics
Scribe Therapeutics is revolutionizing medicine by developing optimized in vivo CRISPR-based genetic medicines designed to become standard of care treatments for patients suffering from highly prevalent diseases, starting with cardiometabolic disease. The company is on a mission to build the first CRISPR-based therapeutics that are effective and safe enough to transform everyone’s lifetime risk for disease. Scribe’s Therapeutics CRISPR by Design™ approach engineers bacterial immune systems into a premier suite of genome and epigenome editing tools built for unique molecular advantages in activity, specificity, and deliverability, enabling the creation of therapies with a broader therapeutic window and safe for use as a preventative treatment.
The company’s lead candidate, STX-1150, is a novel liver-targeted therapy designed to epigenetically silence the PCSK9 gene, resulting in significant and durable reduction of LDL-C levels. To broaden and accelerate the impact of its engineered CRISPR technologies for patients, Scribe Therapeutics has formed strategic collaborations with world-leading pharmaceutical companies including Sanofi and Eli Lilly. Co-founded by Nobel Prize winner Jennifer Doudna and backed by leading life sciences investors, Scribe is engineering the future of genetic medicine. To learn more, visit www.scribetx.com.
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