Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders

Abstract

Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.

Discovery and characterization of novel inhibitors against ALS-related SOD1(A4V) aggregation through screening of a chemical library using Differerential Scanning Fluorimetry (DSF)

“…We decided also to include this application in the contex of Drug repurposing (also known as drug repositioning or therapeutic switching), since, it is more advantageous in comparison to the classic drug discovery process due to the established safety profile of the drug, the shorter duration of the drug development phase and, accordingly the reduced cost along with the limited the risk of failure (Pushpakom et al, 2019; Shah et al, 2021). These features combined with the concomitant cost reduction it includes, creates a major advantage especially for ‘‘orphan diseases’’ like ALS (Pushpakom et al, 2019; Shah et al, 2021).…”

Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

“…One approach could be drug repurposing, which is a highly costeffective and time-saving process of drug development for rare life-threatening neurodegenerative diseases. [105] We believe that drug repurposing utilizing the medicinal chemistry approaches described above, such as tailoring existing molecules, could be more beneficial in unravelling newer NDD targets and improving the PK and pharmacodynamic profile of the drugs. Several approaches can be applied to discover a therapeutic paradigm, such as prodrug approaches, multi-ligand, or targeted approaches, designing compounds which could take advantage of disease pathology, bio-orthogonal approach, chemo selective approach, and/or increasing the pharmacophoric features of molecules.…”

“…Medicinal chemists could find solutions to combat this situation by discovering new molecules by applying various novel approaches. One approach could be drug repurposing, which is a highly cost–effective and time‐saving process of drug development for rare life–threatening neurodegenerative diseases [105] . We believe that drug repurposing utilizing the medicinal chemistry approaches described above, such as tailoring existing molecules, could be more beneficial in unravelling newer NDD targets and improving the PK and pharmacodynamic profile of the drugs.…”

Orally administered niclosamide-based organic/inorganic hybrid suppresses SARS-CoV-2 infection

“…The other approach is a drug repurposing technology [17] by which one can enhance bioavailability of NIC through either physical and/or chemical modification with pharmaceutically inert excipients. This is believed to fuel the drug development process faster since the toxicological profiles are well established [19].…”