Authors: Bruce T. Lamb, Alan David Palkowitz, Gareth Howell, Gregory W. Carter, Paul R. Territo, Adrian L. Oblak, Stacey J. Sukoff Rizzo, Michael Sasner
Published: 2020-12-07
DOI: 10.1002/alz.044157
Source: Full article
AbstractBackgroundDespite considerable efforts, the development of amyloid and tau focused therapies has thus far not yielded compelling positive results in Alzheimer’s disease (AD) clinical trials. In an effort to identify and characterize additional, novel animal models and therapeutic targets for AD, the NIA has funded the Model Organism and Development and Evaluation for Late onset AD (MODEL‐AD) and the Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) consortia and many of the animal models and therapeutic targets are focused on immune pathwaysMethodThe MODEL‐AD consortium has been generating and characterizing novel animal models of late‐onset AD and performing pre‐clinical testing in a subset of models. The recently funded TREAT‐AD consortium seeks to identify and characterize novel therapeutic targets initially focusing on targets nominated by the Accelerating Medicines Partnership for AD (AMP‐AD). The IU/JAX/Pitt AD Precision Models Center (ADPMC) and the IUSM/Purdue AD Drug Discovery Center (ADDDC) part of the MODEL‐AD and TREAT‐AD consortia, respectively, have focused on immune models and targets to accelerate their development as potential therapies for AD.ResultThe IU/JAX/PITT ADPMC has utilized genetic and systems biology data from many of the large AD consortia to prioritize genes and variants to model in animals. This has included a large number of genes/variants in immune pathways including APOE, TREM2, PLCG2, ABCA7, CR1 and others. A subset of the resulting animals have undergone deep phenotyping including histology, fluid biomarkers, brain imaging, behavior, ‐omics and also analysis of the microbiome. The IUSM/Purdue ADDDC has multiple components including a bioinformatics and structural biology core, a structural biology and biophysics core, an assay development and high throughput screening core and a medicinal chemistry and chemical biology core. While the overall strategy and prioritization scheme is still under development, the initial IUSM/Purdue targets will be immune‐focused including INPP5D (SHIP1).ConclusionThrough the coordinated efforts of the NIA‐funded MODEL‐AD and TREAT‐AD consortia, novel AD models and targets will be developed, characterized and made widely available to the scientific community, including a number targeting immune pathways. These efforts are geared to accelerate the development of novel therapeutic targets for AD.