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Single Alkyl Phosphonate Modification of the siRNA Backbone in the Seed Region Enhances Specificity and Therapeutic Profile

ABSTRACT: We evaluated the effect of alkyl phosphonate linkages in enhancing the specificity and therapeutic profile of siRNA when incorporated into the seed region. Modified siRNAs with a single alkyl phosphonate linkage demonstrated improved specificity, particularly when positioned at the internucleotide linkage between positions 6 and 7 from the 5'-end of the guide strand. These modifications maintained robust on-target activity both in vitro and in vivo while significantly reducing off-target effects, as shown by differential gene expression analysis. Additionally, we observed enhanced safety in mice, as evidenced by reduced ALT/AST elevation and the absence of histopathological changes.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE285764 | GEO | 2025/01/15

REPOSITORIES: GEO

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Project description:Spitzoid neoplasms are a challenging group of cutaneous melanocytic proliferations that occur in children or adolescents but can also arise in the elderly. They are characterized by epithelioid and/ or spindle-shaped melanocytes with a stromal background of variable amounts of lymphocytes, blood vessels and sclerosis. According to the WHO 2018 classification, Spitzoid melanocytic lesions are classified as benign Spitz nevi (SN), atypical Spitz tumors (AST) or malignant Spitz tumors (MST). The intermediate AST category represents a diagnostically challenging group since on purely histopathological grounds, their benign or malignant character remains unpredictable. This results in uncertainties in patient management and prognosis. The molecular properties of Spitzoid lesions, especially their transcriptomic landscape, remain poorly understood and genomic alterations in melanoma-associated oncogenes are typically absent. The aim of this study was to characterize the transcriptome of Spitzoid melanocytic neoplasms with digital mRNA expression profiling. Formalin-fixed-paraffin-embedded samples (including 27 SN, 10 AST and 14 MST) were analyzed using the RNA NanoString nCounter PanCancer Pathways Gene Expression panel. The number of significantly differentially expressed genes in SN vs. MST, SN vs. AST and AST vs. MST was 68, 167 and 18, respectively. Gene set enrichment analysis revealed an upregulation of pathways related to epithelial mesenchymal transition, immunomodulatory-, angiogenesis- as well as myogenesis associated processes in AST and MST. In addition, a specific gene expression signature of SN vs. MST was discovered based on the top-ranked six most informative gene expression markers: NRAS, NF1, BMP2, EIF2B4, IFNA17 and FZD9. The AST samples showed intermediate levels of the identified signature. This implies that the identified gene expression signature can potentially be used to distinguish high-grade from low-grade AST. This combined histopathological and transcriptomic methodology is promising for diagnostics of Spitzoid neoplasms and patient management in dermatological oncology in the future.

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Single Alkyl Phosphonate Modification of the siRNA Backbone in the Seed Region Enhances Specificity and Therapeutic Profile

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