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. 2023 May 17;9(2):e12394.
doi: 10.1002/trc2.12394. eCollection 2023 Apr-Jun.

Open drug discovery in Alzheimer's disease

Alison D Axtman  1 , Paul E Brennan  2 , Tristan Frappier-Brinton  3 , Ranjita Betarbet  4 , Gregory W Carter  5 , Haian Fu  4 , Opher Gileadi  6 , Anna K Greenwood  7 , Karina Leal  7 , Frank M Longo  8 , Lara M Mangravite  7 , Aled M Edwards  3 , Allan I Levey  4 ; Emory‐Sage‐SGC TREAT‐AD Center
Affiliations

Open drug discovery in Alzheimer's disease

Alison D Axtman et al. Alzheimers Dement (N Y). .

Abstract

Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature of AD processes suggests that a more diverse, systems-integrated strategy may identify new therapeutic hypotheses. Although many target hypotheses have arisen from systems-level modeling of human disease, in practice and for many reasons, it has proven challenging to translate them into drug discovery pipelines. First, many hypotheses implicate protein targets and/or biological mechanisms that are under-studied, meaning there is a paucity of evidence to inform experimental strategies as well as high-quality reagents to perform them. Second, systems-level targets are predicted to act in concert, requiring adaptations in how we characterize new drug targets. Here we posit that the development and open distribution of high-quality experimental reagents and informatic outputs-termed target enabling packages (TEPs)-will catalyze rapid evaluation of emerging systems-integrated targets in AD by enabling parallel, independent, and unencumbered research.

Keywords: Alzheimer's disease; TEPs; drug development; drug targets; genomics; proteomics; systems biology.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Publication intensity over time for 184 genes reported as associated with Alzheimer's disease (AD) risk.
FIGURE 2
FIGURE 2
Representative histograms of TaRget Enablement to Accelerate Therapy Development for AD (TREAT‐AD) consortium target‐ranking scores encompassing genomics, genetics, and literature evidence for a classical Alzheimer's disease (AD) example target, presenilin1 (PSEN1), as well as a target prioritized by our TREAT‐AD center, spleen‐associated tyrosine kinase (SYK).
FIGURE 3
FIGURE 3
Screenshot depicting the Target Enabling Resources page within the AD Knowledge Portal, found at https://adknowledgeportal.synapse.org/Explore/Target%20Enabling%20Resources.
See this image and copyright information in PMC

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