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-Preclinical data presented at the
-The AATD program, CTX460, is the first investigational candidate to emerge from the SyNTase editing platform and the Company expects to initiate a clinical trial with CTX460 in mid-2026-
-CTX460 showed specific and durable effects, with >90% mRNA correction, a 5-fold increase in total AAT levels, and >99% serum M-AAT:Z-AAT ratio in AATD disease models-
“Alpha-1 antitrypsin deficiency remains an area of significant unmet need, with current treatments unable to address the underlying genetic cause. The goal of therapy should be to normalize alpha-1 antitrypsin levels,” said
AATD is a genetic disorder most commonly caused by a mutation in the SERPINA1 gene, referred to as the Z allele (PiZ, E342K). The majority of patients with severe disease carry two copies of this variant (ZZ genotype). SERPINA1 encodes alpha-1 anti-trypsin (AAT), a protein produced in the liver that protects the lungs by regulating neutrophil elastase, an enzyme that can damage lung tissue if left uncontrolled.
In AATD, the PiZ mutation (SERPINA1-E342K) produces a misfolded form of AAT, known as Z-AAT, which accumulates in the liver as misfolded AAT polymers that can contribute to fibrosis and cirrhosis. At the same time, insufficient circulating functional AAT, which is produced by the wild-type M allele (M-AAT), leaves the lungs vulnerable to emphysema and other serious diseases. Patients with two Z alleles, typically have serum AAT levels of ~5-6 mM, whereas normal levels are usually at least 4-fold higher (>20mM). The current standard-of-care requires weekly intravenous (IV) infusion of purified functional M-AAT protein to mitigate lung disease symptoms, but no approved therapies address the underlying genetic cause. Better therapies are needed that can normalize AAT levels to minimize risk of lung disease progression.
CTX460 is a SyNTase editing-based investigational candidate targeting the E342K mutation in SERPINA1, encapsulated in a de-risked, proprietary lipid nanoparticle (LNP). The preclinical data presented today evaluated CTX460 in two preclinical models of AATD: the well-established NSG-PiZ mouse model, which carries human SERPINA1 Z alleles, and a novel humanized PiZ rat model in which the normal rat SERPINA1 gene is replaced with the human mutant SERPINA1 E342K variant. These models were used to evaluate gene and mRNA correction, serum protein levels, and durability of effect following a single dose of CTX460.
CTX460 Key Preclinical Data Highlights
- A single dose of CTX460 achieved significant, dose-dependent correction of liver DNA in both rat and mouse AATD models, with near saturating editing in hepatocytes at doses as low as 0.1 mg/kg. Furthermore, a single dose of CTX460 was able to achieve >90% mRNA correction at a clinically relevant dose of 0.5 mg/kg in PiZ mice.
- Relative to pre-dose values, editing with CTX460 yielded a >5-fold increase in total serum AAT levels with an M-AAT:Z-AAT ratio of over 99% in the serum of PiZ rats. AAT upregulation was linearly correlated with editing efficiency.
- Durability of editing was maintained in both rat and mouse models for up to 7 weeks and 9 weeks, respectively.
Together, these data provide preclinical proof-of-concept for a potential best-in-class approach to address the underlying cause of AATD and support the use of SyNTase editing as a promising platform for the treatment of both rare and common disorders.
About CRISPR Therapeutics
Since its inception over a decade ago, CRISPR Therapeutics has evolved from a research-stage company advancing gene editing programs into a leader that celebrated the historic approval of the first-ever CRISPR-based therapy. The Company has a diverse portfolio of product candidates across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine, cardiovascular, autoimmune, and rare diseases. In 2018, CRISPR Therapeutics advanced the first-ever CRISPR/Cas9 gene-edited therapy into the clinic to investigate the treatment of sickle cell disease and transfusion-dependent beta thalassemia. Beginning in late 2023, CASGEVY® (exagamglogene autotemcel [exa-cel]) was approved in several countries to treat eligible patients with either of these conditions. The Nobel Prize-winning CRISPR technology has revolutionized biomedical research and represents a powerful, clinically validated approach with the potential to create a new class of potentially transformative medicines. To accelerate and expand its efforts, CRISPR Therapeutics has formed strategic partnerships with leading companies including Vertex Pharmaceuticals. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Boston, Massachusetts and San Francisco, California. To learn more, visit www.crisprtx.com.
CRISPR Therapeutics Forward-Looking Statement
Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements made by
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Source: CRISPR Therapeutics AG