Phenotypic Screens Targeting Neurodegenerative Diseases

Abstract

Neurodegenerative diseases affect millions of people worldwide, and the incidences increase as the population ages. Disease-modifying therapy that prevents or slows disease progression is still lacking, making neurodegenerative diseases an area of high unmet medical need. Target-based drug discovery for disease-modifying agents has been ongoing for many years, without much success due to incomplete understanding of the molecular mechanisms underlying neurodegeneration. Phenotypic screening, starting with a disease-relevant phenotype to screen for compounds that change the outcome of biological pathways rather than activities at certain specific targets, offers an alternative approach to find small molecules or targets that modulate the key characteristics of neurodegeneration. Phenotypic screens that focus on amelioration of disease-specific toxins, protection of neurons from degeneration, or promotion of neuroregeneration could be potential fertile grounds for discovering therapeutic agents for neurodegenerative diseases. In this review, we will summarize the progress of compound screening using these phenotypic-based strategies for this area, with a highlight on unique considerations for disease models, assays, and screening methodologies. We will further provide our perspectives on how best to use phenotypic screening to develop drug leads for neurodegenerative diseases.

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…For instance, Chong et al [14] assembled a library of 2687 existing drugs collected worldwide (known as John Hopkins University Clinical Compound Library) and performed phenotypic screening for parasite inhibition. A number of clinical library collections are now available through commercial sources: National Institutes of Health (NIH) Clini c a l C o l l e c t i o n s t h r o u g h E v o t e c ( h t t p : / / w w w. nihclinicalcollection.com), subsets of the compound collections from Microsource (e.g., Pharmakon1600, Spectrum, National Institute of Neurological Disorders and Stroke custom collection II and US and international drug collections), Sigma (e.g., LOPAC1280), Preswick, Selleckchem, Enzo Life Sciences, and Tocris (e.g., Tocriscreen) [15]. The NIH Chemical Genomics Center also built a collection of drugs approved in the USA and other foreign countries [16].…”

“…Once successful PDD is performed and identifies promising hit compounds, traditional target-directed or mechanism-based secondary assays are performed, followed by preclinical animal testing. For complex neurodegenerative disorders, such as AD, where molecular targets and disease mechanisms are far less clear, phenotypic assays can play an important role for selecting therapeutic leads that can effectively modify a disease-specific pathway [15,20,21]. A small number of studies have attempted to conduct phenotypic screening relevant to AD, mainly by examining amyloid precursor protein (APP) and APP metabolites, including amyloid β-peptide (Aβ), using libraries of a few hundred Food and Drug Administration (FDA)-approved drugs in neuronal cell lines [22][23][24].…”

“…As physiological context is crucial for establishing predictive in vitro models for AD phenotypic screening, there is an increasing need for more physiological models, such as primary brain cells or stem cell-derived neurons or glial cells, which are scalable and robust for high throughput screening (HTS) assays [15,20,33,38]. Small molecule screenings for Aβ biogenesis and Aβ toxicity have been described in mouse embryonic stem cellderived pyramidal neurons and commercial human induced pluripotent stem (iPS) cell-derived neurons [33,39].…”

Phenotypic screening with primary neurons to identify drug targets for regeneration and degeneration

“…Despite this dominance, phenotypic (cell-based) screening has recently made a comeback, as an approach to discover biologically active hits relevant to a biological process or therapeutic outcome (Lee and Bogyo, 2013). In particular, phenotypic screening of neural cells offers a way to find compounds or gene targets that modulate the key phenotypes of neurodegeneration and neuroregeneration, without the requirement for the detailed mechanistic knowledge that is often lacking in complex neurological disorders (Zhang et al, 2014; Swinney and Anthony, 2011; Khurana et al, 2015; Rosamond and Allsop, 2000). Multiple neurodegenerative diseases have been studied both with target-based and phenotypic-based screens, including Alzheimer’s Disease (AD; Bettens et al, 2010), Parkinson’s Disease (PD; Cookson and Bandmann, 2010), bipolar disease, autism, and schizophrenia (Haggarty et.…”

The Use of Antibodies in Small-Molecule Drug Discovery

“…This approach has been applied successfully to identify new molecules that inhibit pathways involved in pathology, including infection 33 and neurodegenerative disease. 34,35 The application of antibodies as pharmacologic tools in phenotypic screens offers great potential to complement a small-molecule approach and to identify antibody tools that can be used to deconvolute novel targets.…”