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Using Human Differentially Expressed Gene Lists to Perform Downstream Pathway Enrichment Analysis and Target Prioritization

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Identifying therapeutic drug targets using bidirectional effect genes.

Karol Estrada¹, Steven Froelich², Arthur Wuster²

¹BioMarin Pharmaceutical Inc., Novato, CA, USA. contact@karolestrada.com.

Nature Communications

|April 14, 2021

Summary

This summary is machine-generated.

Identifying drug targets is challenging. We found that genes with bidirectional effects (gain and loss of function mutations) are more likely to lead to successful therapeutics, particularly for idiopathic short stature.

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Published on: December 11, 2016

Area of Science:

Genetics
Pharmacology
Biotechnology

Background:

Prioritizing genes for therapeutic development is difficult.
Identifying drug targets with a high probability of success is crucial for common diseases.

Purpose of the Study:

To propose a novel approach for identifying high-success drug targets.
To validate the therapeutic potential of targeting genes with bidirectional effects.

Main Methods:

Developed the Bidirectional Effect Selected Targets (BEST) approach, focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations.
Analyzed 98 BEST genes across various indications.
Investigated five specific genes (IGF1R, NPPC, NPR2, FGFR3, SHOX) associated with stature.
Conducted functional experiments using a CNP analog.

Main Results:

Drugs targeting BEST genes showed a 3.8-fold higher approval rate compared to non-BEST genes.
Rare variants in the five stature-related genes significantly increased the risk for idiopathic short stature (ISS).
An exogenous CNP analog (encoded by NPPC) successfully rescued the ISS phenotype in functional experiments.

Conclusions:

The BEST approach effectively identifies drug targets with a higher likelihood of clinical success.
Targeting genes with bidirectional effects offers a promising strategy for drug discovery.
CNP analog therapy shows potential for treating idiopathic short stature.