High-throughput drug screens for amyotrophic lateral sclerosis drug discovery

ABSTRACT

Introduction: Amyotrophic lateral sclerosis (ALS) is a rapid adult-onset neurodegenerative disorder characterised by the progressive loss of upper and lower motor neurons. Current treatment options are limited for ALS, with very modest effects on survival. Therefore, there is a unmet need for novel therapeutics to treat ALS.

Areas covered: This review highlights the many diverse high-throughput screening platforms that have been implemented in ALS drug discovery. The authors discuss cell free assays including in silico and protein interaction models. The review also covers classical in vitro cell studies and new cell technologies, such as patient derived cell lines. Finally, the review looks at novel in vivo models and their use in high-throughput ALS drug discovery

Expert opinion: Greater use of patient-derived in vitro cell models and development of better animal models of ALS will improve translation of lead compounds into clinic. Furthermore, AI technology is being developed to digest and interpret obtained data and to make ‘hidden knowledge’ usable to researchers. As a result, AI will improve target selection for high-throughput drug screening (HTDS) and aid lead compound optimisation. Furthermore, with greater genetic characterisation of ALS patients recruited to clinical trials, AI may help identify responsive genetic subtypes of patients from clinical trials.

KEYWORDS:

• Amyotrophic lateral sclerosis (ALS)
• drug discovery
• high-throughput drug screening (HTDS)

Article highlights

• Amyotrophic lateral sclerosis (ALS) is a rapid adult-onset neurodegenerative disorder.

• The current treatments for patients with ALS are modest in effect and there is a need for better treatments for this devastating disease

• A large number of high-throughput drug screens have been performed to identify novel ALS therapeutics

• Screens have been performed using a wide range of different model systems, various genetic subtypes of ALS, as well as aiming for a wide range of different molecular targets and/or phenotypic outcomes - highlighting the complexity of ALS and necessity for careful study design

• Greater use of patient-derived in vitro cell models and development of better animal models of ALS will improve translation of lead compounds into clinic

This box summarizes key points contained in the article.

Declaration of interest

M Stopford is funded by BenevolentAI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.