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Background: Our previous study identified that Sildenafil (a phosphodiesterase type 5 [PDE5] inhibitor) is a candidate repurposable drug for Alzheimer's Disease (AD) using in silico network medicine approach. However, the clinically meaningful size and mechanism-of-actions of sildenafil in potential prevention and treatment of AD remind unknown.
Method: We conducted new patient data analyses using both the MarketScan® Medicare with Supplemental database (n = 7.
Drug Development.
Alzheimers Dement
December 2024
The University of Texas Health Science Center at Houston, Houston, TX, USA.
Background: Developing drugs for treating Alzheimer's disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies.
Method: To address the challenge in AD drug development, we developed a multi-task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates RESULT: Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase 2/3 clinical trials.
Drug Development.
Alzheimers Dement
December 2024
Case Western Reserve University, Cleveland, OH, USA.
Background: Traumatic Brain Injury (TBI) is one of the most common nonheritable causes of Alzheimer's disease (AD). However, there is lack of effective treatment for both AD and TBI. We posit that network-based integration of multi-omics and endophenotype disease module coupled with large real-world patient data analysis of electronic health records (EHR) can help identify repurposable drug candidates for the treatment of TBI and AD.
View Article and Find Full Text PDFBackground: Small, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents in Alzheimer's disease (AD). In the last few years, Aprile and co-workers designed and purified a single-domain antibody (sdAb), called DesAb-O, with high specificity for Aβ oligomeric conformers. Recently, Cascella and co-workers showed that DesAb-O can selectively detect synthetic Aβ oligomers both in vitro and in cultured cells, neutralizing their associated neuronal dysfunction.
View Article and Find Full Text PDFIt is well recognised that Alzheimer's disease and related dementia disorders (ADRD) are associated with very high societal costs. The total global costs of dementia have been estimated to over 1.3 trillion US$ annually (Wimo, Seeher et al.
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