Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders.

Sweta Shah,Sofia Amaral-Garcia,Marc Marie Dooms,Mariana Igoillo-Esteve

doi:10.3389/fphar.2021.768023

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.

Highlights

The four rare neurodegenerative diseases taken as example in this study clearly highlight the limited availability of approved therapies for the management of rare pathologies, harnessing the importance of drug repurposing–based approaches to fill these gaps
The identification of repurposed drugs with potential therapeutic benefit involves experimental or in silico approaches that depend on a good understanding of the molecular disease mechanisms, highlighting the key role of fundamental research in the process
The utilization of patient stem cell–based high-throughput screening approaches and in silico prediction tools such as network mapping, genome-wide association studies, (GWAS) and rare variant association studies (RVAS) significantly accelerated the identification of candidate drugs for disease treatment. Despite these very good advances that helped identify promising drugs for the treatments of different rare diseases, including Huntington’s disease (HD), Friedreich’s ataxia (FRDA), Wolfram syndrome, and Amyotrophic Lateral Sclerosis (ALS), there is still an important translational gap between the volume of preclinical and clinical research conducted and the number of repurposed approved drugs. This is the consequence of several factors, for example, the complexity of organizing clinical trials in rare diseases due to reduced patient number, their wide geographical distribution, their short life span, and the severity of the diseases that complicate the study design, the determination of the relevant clinical endpoints, and the ethical concerns in introducing a placebo group in the trial which, if present, may discourage the patients to participate in the study, and if absent will reduce the validity of the trial

Summary

Introduction

Rare neurodegenerative diseases are low-prevalent, life-threatening, or chronically debilitating disorders, caused by pathogenic mutations in a single gene or by particular environmental insults (e.g., pesticides, metals, air pollution, endotoxins, and prions, among others), triggering progressive neuronal dysfunction and loss of specific groups of neurons (Matilla-Duenas et al, 2017). Depending on the disease etiology, distinct parts of the central nervous system may be affected, resulting in impaired motor and cognitive function with a significant impact on the quality of life of the affected individuals (Matilla-Duenas et al, 2017). In the last few years, the advances in next-generation sequencing (NGS) have importantly accelerated the identification of disease-causing genes. Despite the advances in generation sequencing (NGS), data analysis, and other technologies that importantly contribute to identify the mutated genes and understand the biology of rare diseases and

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Conclusion