‘High-Risk, High-Reward’ Approach To Finding Alzheimer’s Disease Treatments
By Deborah Borfitz
October 19, 2020 | The quest to find new medicines for Alzheimer’s disease (AD) may finally make some headway, thanks to a Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) project that is taking a “high-risk, high-reward” approach to diversifying the drug development pipeline, according to Lara Mangravite, president of Sage Bionetworks. The Seattle-based nonprofit is partnered with Emory University and the Structural Genomics Consortium (SGC) on the initiative.
AD is a complex and common disease, affecting 54 million people globally and rising, with a paucity of treatment options, says Mangravite, who spoke on the topic at the recent Bio-IT World Conference & Expo Virtual. Part of the problem is that a handful of hypotheses are getting repeatedly evaluated. Clinical trials for AD are also quite lengthy and expensive because it is such a long progressing disease.
Thanks to the National Institute on Aging (NIA), congressional mandates, private funders, and foundations, there is also a wealth of financial support for AD research that didn’t exist a decade ago, she adds. TREAT-AD, with more than $73 million in NIA funding, is endeavoring to cast light on a more varied set of hypotheses where there is currently a dearth of evidence in the literature. A second TREAT-AD research center pairs Indiana University School of Medicine with Purdue University, and the two projects share the funding pot.
Proteomic-based analyses of brain samples from Alzheimer’s patients suggest “a whole series of biological dysregulation is going on,” many of which may be useful to examine, Mangravite says. Since only a small fraction of the genetic variants have been identified in prior AD genome-wide association studies (GWAS) conducted around the world, either GWAS needs to be complemented by other approaches or many more people need to be sampled.
Using a multi-omics dataset, the public-private Accelerating Medicines Partnership (AMP) has been finding promising biological targets of diseases, including Alzheimer’s. In the absence of industry standards, the field has to date found it difficult to achieve consensus across the outputs of different research groups, says Mangravite. But after five years, AMP-AD has nominated a series of hypotheses about what is causal to disease and the list is posted on the Agora website hosted and maintained by Sage Bionetworks.
Datasets generated by AMP-AD investigators undergo consensus evaluation by all network model algorithms, continues Mangravite. Of the five main areas of biological signaling found to be dysregulated via bioinformatics analysis, two have been previously understudied and are now the team’s primary focus.
To catalyze more research in these promising new domains, SGC has created well-validated reagents and made them freely available for use by investigators. The initiative is just getting started, she says. All tools and materials generated by TREAT-AD will be shared without restriction, and no patents will be issued.
The microglial protein called moesin has been associated with neuropathology within the Alzheimer’s brain, notes Mangravite. Bayesian analysis has identified the key drivers and genetics suggest it is causal for AD.
To prioritize “dark targets” in an unbiased fashion, the research team has developed a rubric that combines data from different sources to create a novelty score indicating how much a hypothesis has already been studied. That keeps the focus on targets with almost no supportive evidence.
The hypotheses being actively investigated implicate four protein-coding genes—VGF, CLU, DNM1 and INPP5—for which reagents are now being developed. TREAT-AD is intentionally “putting the cart before the horse,” says Mangravite. “Conventional wisdom says you don’t start medicinal chemistry until the target has been validated. We say that having the highest quality tools can help explore therapeutic hypotheses in a realistic context.”
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