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Selection of Potential Pharmacological Targets in ALS Based on Whole- Genome Expression Profiling
Giovanna Morello, Francesca Luisa Conforti, Rosalba Parenti
1Istituto di Scienze Neurologiche, CNR, Via Paolo Gaifami, 18, 95125 Catania, Italy. sebastiano.cavallaro@cnr.it.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by the gradual degeneration and death of upper and lower motor neurons. Despite continue efforts, the etiology and pathogenesis of ALS are not well understood yet. The lack of knowledge about molecular and cellular players involved in the neurodegenerative progression of ALS hinders effective therapy development. Several genomicbased studies have been conducted to identify genetic contributors to sporadic ALS (SALS) and new potential pharmacological targets, but these have resulted in short and non-overlapping lists of candidates. In the last few years, our research group has developed the largest whole-genome expression profile database of SALS human samples. We have identified several genes deregulated in the motor cortex of SALS patients and analyzed the role of these genes within deregulated pathways, providing a full molecular portrait of ALS pathogenesis. Some of deregulated genes encode for proteins that are direct or indirect targets of experimental or therapeutic drugs already applied to unrelated diseases. In this review, we focus on the potential role of candidate targets in ALS pathophysiology, highlighting their possible contribution to ALS therapy. The rational selection of the most promising drug targets and related modulatory drugs may provide a starting point for their preclinical or clinical validation and, hopefully, the development of more effective treatments for ALS patients.
Insights
Researchers identified deregulated genes in sporadic Amyotrophic Lateral Sclerosis (ALS) motor cortex, revealing potential therapeutic targets. This molecular portrait offers new avenues for developing effective ALS treatments.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss.
- The precise etiology and pathogenesis of ALS remain poorly understood, impeding therapeutic advancements.
- Existing genomic studies for sporadic ALS (SALS) have yielded limited, non-overlapping candidate genes.
Purpose of the Study:
- To present a comprehensive molecular portrait of ALS pathogenesis using the largest whole-genome expression profile database of SALS human samples.
- To identify deregulated genes and pathways in the motor cortex of SALS patients.
- To explore the therapeutic potential of identified candidate targets and drugs for ALS treatment.
Main Methods:
- Development of the largest whole-genome expression profile database for SALS human samples.
- Identification of deregulated genes in the motor cortex of SALS patients.
- Analysis of deregulated pathways and candidate gene-drug target relationships.
Main Results:
- Identification of several genes deregulated in the motor cortex of SALS patients.
- Characterization of deregulated pathways contributing to ALS pathogenesis.
- Discovery that some deregulated genes encode targets of existing experimental or therapeutic drugs.
Conclusions:
- The identified deregulated genes and pathways provide a detailed molecular understanding of ALS.
- Candidate targets linked to existing drugs offer a promising starting point for ALS therapy development.
- Rational selection of drug targets and modulatory drugs may accelerate preclinical and clinical validation for more effective ALS treatments.
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