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A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation.

ABSTRACT: Protein degradation techniques, such as proteolysis-targeting chimeras (PROTACs) and lysosome-targeting chimeras (LYTACs), have emerged as promising therapeutic strategies for the treatment of diseases. However, the efficacy of current protein degradation methods still needs to be improved to address the complex mechanisms underlying diseases. Herein, a LYTAC Plus hydrogel engineered is proposed by nucleic acid self-assembly, which integrates a gene silencing motif into a LYTAC construct to enhance its therapeutic potential. As a proof-of-concept study, vascular endothelial growth factor receptor (VEGFR)-binding peptides and mannose-6 phosphate (M6P) moieties into a self-assembled nucleic acid hydrogel are introduced, enabling its LYTAC capability. Small interference RNAs (siRNAs) is then employed that target the angiopoietin-2 (ANG-2) gene as cross-linkers for hydrogel formation, giving the final LYTAC Plus hydrogel gene silencing ability. With dual functionalities, the LYTAC Plus hydrogel demonstrated effectiveness in simultaneously reducing the levels of VEGFR-2 and ANG-2 both in vitro and in vivo, as well as in improving therapeutic outcomes in treating neovascular age-related macular degeneration in a mouse model. As a general material platform, the LYTAC Plus hydrogel may possess great potential for the treatment of various diseases and warrant further investigation.

SUBMITTER: Huang Y

PROVIDER: S-EPMC10987141 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation.

Huang Yangyang Y Zhou Xujiao X Zhang Yirou Y Xie Miao M Wang Fujun F Qin Jingcan J Ye Han H Zhang Hong H Zhang Chuan C Hong Jiaxu J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240122 13

Protein degradation techniques, such as proteolysis-targeting chimeras (PROTACs) and lysosome-targeting chimeras (LYTACs), have emerged as promising therapeutic strategies for the treatment of diseases. However, the efficacy of current protein degradation methods still needs to be improved to address the complex mechanisms underlying diseases. Herein, a LYTAC Plus hydrogel engineered is proposed by nucleic acid self-assembly, which integrates a gene silencing motif into a LYTAC construct to enha ...[more]

PMID: 38251411

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Project description:Blood-based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer's disease. Specifically, phosphorylated-tau variants (p-tau181, p-tau217 and p-tau231) are promising biomarkers for identifying Alzheimer's disease pathology. Antibody-based assays such as single molecule arrays immunoassays are powerful tools to investigate pathological changes indicated by blood-based biomarkers and have been studied extensively in the Alzheimer's disease research field. A novel proteomic technology-NUcleic acid Linked Immuno-Sandwich Assay (NULISA)-was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for 120 protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying Alzheimer's disease biomarkers, validation through comparisons with more established methods is required. The main objective of the current study was to determine the capability of p-tau variants quantified using NULISA for identifying abnormal amyloid-β and tau pathology. We assessed 397 participants [mean (standard deviation) age, 64.8 (15.7) years; 244 females (61.5%) and 153 males (38.5%)] from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p-tau181, p-tau217 and p-tau231 from NULISA and single molecule arrays immunoassays. Participants also underwent neuroimaging assessments, including structural MRI, amyloid-PET and tau-PET. Our findings suggest an excellent agreement between plasma p-tau variants quantified using NULISA and single molecule arrays immunoassays. Plasma p-tau217 measured with NULISA shows excellent discriminative accuracy for abnormal amyloid-PET (area under the receiver operating characteristic curve = 0.918, 95% confidence interval = 0.883 to 0.953, P < 0.0001) and tau-PET (area under the receiver operating characteristic curve = 0.939; 95% confidence interval = 0.909 to 0.969, P < 0.0001). It also presents the capability for differentiating tau-PET staging. Validation of the NULISA-measured plasma biomarkers adds to the current analytical methods for Alzheimer's disease diagnosis, screening and staging and could potentially expedite the development of a blood-based biomarker panel.

Dataset Information

A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation.

Publications

A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation.

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