Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis.

Francesco Bellomo,Laura Rita Rega,Gianna Di Giovamberardino,Diego Di Bernardo,Laura Giaquinto,Anna Pastore,Maria Antonietta De Matteis,Diego Luis Medina,Anna Taranta,Sandro Montefusco,Ester De Leo,Francesco Emma

doi:10.3390/ijms222312829

Abstract

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

Highlights

Rare diseases have increasingly become a public health priority [1]
High Throughput Screening Based on Cell Cystine Content
The analysis identified significant modulation of genes associated with extracellular matrix structural components (GO:0005201), with transmembrane transporter activity (GO:0022857) and calcium binding and signaling (GO:0005509) (Figure 4A)

Summary

Introduction

Rare diseases have increasingly become a public health priority [1]. Epidemiological data show that taken together, rare diseases affect between 3.5% and 5.9% of the global population [1]. The high number and the heterogeneity of rare diseases limit the interest of pharmaceutical industries in the development of new treatments. To this end, drug-repositioning strategies using cell-based phenotypic assays in combination with bioinformatics analysis tools, may represent successful strategies to identify new therapies [2]. Nephropathic cystinosis [OMIM #219800] is a rare genetic disorder that develops during the first months of life, causing end-stage kidney disease and other extra-renal complications that are secondary to lysosomal cystine accumulation [3,4]. Cysteamine treatment facilitates clearance of lysosomal cystine and is the current standard of care for

Methods

Results

Conclusion