Potential of CRISPR-based Genome Editing for Vascular Diseases with Sustained Therapeutic Effects After Single Administration
Background
Vascular diseases (including arterial, venous, and pulmonary diseases) are major contributors to global mortality and morbidity. While conventional pharmacological and surgical therapies have advanced, endothelial dysfunction and chronic inflammation remain significant factors driving disease progression. Patients often face the burden of lifelong medication, along with the risk of long-term adverse effects. Furthermore, vascular diseases with genetic origins lack definitive treatment options.
In this context, third-generation CRISPR/Cas9 gene editing technology has emerged as a promising alternative. This technology aims to directly modify disease-causing pathways at the genomic level, potentially overcoming the limitations of existing therapies.
Key Findings
A systematic review, guided by the PRISMA 2020 guidelines, identified 17 studies that applied CRISPR/Cas9 technology to vascular diseases. The analysis included in vitro studies, animal models, and early-phase clinical trials targeting endothelial cell regulation, inflammatory responses, lipid metabolism, and genetic vascular diseases. The data revealed that key genes involved in disease progression and repair were targeted for genome editing.
Specifically, targets included proprotein convertase subtilisin/kexin type 9 (PCSK9), hypoxia-inducible factor 1 alpha (HIF1A), NOD-like receptor protein 3 (NLRP3), which regulate lipid metabolism and inflammatory responses, respectively. Additionally, various experimental approaches targeted nitric oxide synthase 3 (NOS3), methyltransferase-like protein 4 (METTL4), bone morphogenetic protein receptor type 2 (BMPR2), and alpha-smooth muscle actin (ACTA2). Genome editing resulted in improved endothelial cell repair, reduced chronic inflammation, and normalized lipid metabolism.
Notably, early clinical studies in patients demonstrated that a single in vivo administration of CRISPR-based therapeutics resulted in sustained gene silencing. This represents a significant improvement in terms of treatment convenience and durability compared to existing therapies.
Significance and Future Directions
The findings of this gene editing study suggest the potential to shift the paradigm of treating refractory vascular diseases from management to cure. The concrete data demonstrating sustained gene expression control with a single administration will likely serve as a crucial foundation for the development of novel cardiovascular therapeutics. From an industrial perspective, this could also herald the emergence of a new market for therapies that achieve fundamental treatment with a single administration.
However, challenges remain in translating this technology to clinical practice. Off-target effects, where unintended genes are edited, must be completely eliminated, and a safe and effective delivery system for the therapeutic agent to target cells needs to be established. The initially high cost of treatment may also limit patient access, necessitating technological improvements and the development of supportive measures such as health insurance coverage.
Despite advances in therapy, arterial, venous, and pulmonary vascular diseases remain leading causes of morbidity and mortality. Persistent endothelial dysfunction, inflammation, oxidative stress, and maladaptive vascular remodeling continue to drive disease progression and residual risk. CRISPR/Cas9 technology offers a unique opportunity to modify the molecular pathways underlying vascular pathophysiology directly. The PRISMA 2020 guidelines guided the systematic review. The databases PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and Google Scholar were searched from their inception until September 2025 for experimental and/or clinical studies evaluating the application of CRISPR/Cas9 on vascular disease. Included were in vitro studies, animal model studies, and early-phase human studies aimed at targeting the endothelial cell regulatory pathways, inflammatory pathways, metabolic remodeling processes, and hereditary causes of vasculopathy. Seventeen studies met the inclusion criteria. CRISPR technologies targeting PCSK9, NOS3, HIF1A, NLRP3, METTL4, BMPR2, and ACTA2 were identified to enhance repair mechanisms in endothelial cells, regulate inflammation, modulate lipid metabolism, and remodel the vascular system. The human studies demonstrated sustained gene silencing effects following a single dose of CRISPR-induced in vivo editing. The use of CRISPR technology to edit cell genomes offers potential to alter disease progression in vascular medicine, with a growing body of translational evidence supporting the feasibility and durability of the approach.
This research provides a concrete treatment strategy for patients with hereditary hypercholesterolemia or refractory pulmonary hypertension. Existing antibody therapies require lifelong administration with injections every few weeks or months, imposing significant economic and physical burdens on patients. In contrast, CRISPR therapy involves a single intravenous administration to permanently inactivate the PCSK9 gene in hepatocytes, reducing serum low-density lipoprotein (LDL) cholesterol levels to normal levels. This reduces the burden of repeated hospital visits for patients and significantly improves the overall efficiency of the healthcare system. Furthermore, it is expected to provide a fundamental clinical solution for breaking the cycle of inherited cardiovascular diseases within affected families.