# Expanding the Druggable Human Genome

> **NIH NIH F31** · IOWA STATE UNIVERSITY · 2024 · $19,872

## Abstract

PROJECT SUMMARY: Most small molecule drugs elicit their effects by modulating protein function, despite the
fact that only a small portion of the genome is translated (~1-2%). Further, only ~15% of the human proteome is
considered to be druggable, severely limiting therapeutic pipelines. The scientific challenge is to develop
generalizable methods to drug the other ~85% of coding genes. The purpose of this proposal is to advance a
radically new paradigm to expand the druggability of the (protein coding) genome by targeting disease-causing
genes at the level of their RNA. To do so, we will computationally and biochemically determine RNA secondary
structures in the transcriptome, with a focus on disease associated genes, to aid in the design of drug-like small
molecules to treat diseases at the RNA level. This innovative approach for targeting the transcriptome could
massively expand our ability to treat a wide array of diseases, spanning from genetic disorders to cancer and
pathogenic infections, and expanding the repertoire of drug action.
 The proposed studies synergize the expertise of two laboratories. Dr. Walter Moss’ Lab (sponsor) has
developed and implemented robust approaches to precisely define conserved and functional RNA structures
throughout the human genome. Dr. Matthew Disney’s lab (co-sponsor) has established a comprehensive
program for the design of small molecules that selectively target RNA and modulate disease biology, including
those that selectively recruit endogenous nucleases to a desired transcript. Collectively, our synergistic areas of
expertise will allow us to define the druggable human genome, drug undruggable protein targets at the level of
their mRNAs, and push forward a bench-to-bedside, precision medicine paradigm.
 In Aim 1, we will define conserved RNA structures throughout the genome, with a focus on validating and
targeting conserved structures in mRNAs that encode proteins that are considered undruggable. These studies
will define evolutionary conservation across vertebrate genomes to provide key insights into both biology and
druggability. We will evaluate and improve model structures using in cellulis RNA structure probing to test
predictions and, where needed, provide constraints that can be used to create experimentally informed revised
models. In Aim 2 we will generate a list of high value motifs with the highest probability of being druggable,
perform functional analyses to determine their effects on gene expression, and deduce interactions.

## Key facts

- **NIH application ID:** 10817131
- **Project number:** 5F31CA257090-04
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Warren B Rouse
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $19,872
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-10-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817131

## Citation

> US National Institutes of Health, RePORTER application 10817131, Expanding the Druggable Human Genome (5F31CA257090-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817131. Licensed CC0.

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