Choi, Y.-H. | bioRxiv Science

bioRxiv2025

Clonal Hematopoiesis Mutations Increase Risk of Alzheimer's Disease with APOE ϵ3/ϵ3 Genotype

Clonal hematopoiesis of indeterminate potential (CHIP) represents clonal expansion of blood cells, and increases the risk of hematological malignancies and cardiovascular disorders. Recent studies have studied CHIP mutations in individuals with Alzheimers disease (AD), but it is unclear whether their role in AD pathogenesis is protective, detrimental, or neutral. In this study, we used molecular-barcoded deep gene panel sequencing ([~]400X) to examine CHIP mutations in 298 blood samples from AD and neurotypical individuals 60 years and older. The AD patients exhibited a significantly higher burden of CHIP mutations compared to the age-matched controls (p < 2e-7, odds ratio (OR) = 2.89), particularly in low-frequency variants often not captured by standard whole exome or whole genome sequencing (WGS). This increase was driven by individuals with the APOE {varepsilon}3/{varepsilon}3 genotype and absent in {varepsilon}4 carriers. Analysis of an independent dataset from the Alzheimers Disease Sequencing Project (ADSP), comprised of WGS data from [~]30,000 individuals, confirmed increased CHIP mutations in AD versus control (p < 0.02, OR = 1.32), again driven by individuals with APOE {varepsilon}3/{varepsilon}3 genotype. CHIP mutations in AD patients also showed stronger positive selection than in controls. Our results indicate that AD patients show significantly more CHIP mutations in their blood than controls, involving more than one third of AD patients, and contributing to AD risk through a mechanism independent of APOE {varepsilon}4.

genetics↗

bioRxiv2023

The defined TLR3 agonist, Nexavant, exhibits anti-cancer efficacy and potentiates anti-PD-1 antibody therapy by enhancing immune cell infiltration.

Nexavant has been reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. Nexavants distinct nature, compared to Poly(I:C), was evident through precise quantification, thermostability, and resistance to RNase A. Unlike Poly (I: C) which activates TLR3, RIG-I and MDA5, Nexavant stimulates the signaling through TLR3 and RIG-I but not MDA5. Intratumoral Nexavant treatment led to a unique immune response compared to Poly(I:C), immune cell infiltration, and suppression of tumor growth in various animal cancer models. Nexavant therapy outperformed anti-PD-1 antibody treatment in all tested models and showed a synergistic effect in combinational therapy, especially in well-defined cold tumor models. The effect was similar to Nivolumab in a humanized mouse model. Intranasal instillation of Nexavant recruited immune cells (NK, CD4+ T, CD8+ T) to the lungs, suppressing lung metastasis and improving animal survival. Our study highlighted Nexavants defined nature for clinical use, unique signaling pathways, and its potential as a standalone anti-cancer agent or in combination with anti-PD-1 antibody. Simple SummaryNexavant, a newly reported TLR3 agonist, has advantages over Poly(I:C) in quality control and pre-clinical efficacy. Here, we further investigated Nexavants physicochemical properties, downstream signaling pathways, anti-cancer efficacy, and mechanism of action. Nexavant was homogenous in solution, less sensitive to RNase A, and showed thermostability compared with Poly(I:C). Unlike Poly(I:C), the TLR3, RIGI, and MDA5 activator, Nexavant only activated TLR3 and RIG-I but not MDA5. Administration of Nexavant either by intratumoral or intranasal route suppressed tumor growth in various cancer models. Combination therapy with anti-PD-1 antibody exhibited synergistic tumor growth inhibition than the respective monotherapies. This study demonstrated that Nexavant could be more suitable for clinical use over Poly(I:C) and applied as an anti-cancer agent in the presence or absence of an anti-PD-1 antibody.

immunology↗