# Small Molecules to Promote Regeneration and Recovery Following Spinal Cord Injury

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2022 · —

## Abstract

A. ABSTRACT
A significant impediment towards improvement of outcome after spinal cord injury (SCI) is the limited axonal
regeneration due to insufficient regrowth of the axonal fibers at the lesion site. Signaling mediated by RhoA
GTPases presents a significant impediment to growth. To date, there exists no small-molecule RhoA antagonists
that have shown in vivo efficacy. This is attributed to the fact that small GTPases like RhoA do not have druggable
pockets, making the development of small molecules that directly bind to them extremely difficult. However, over
the years, several proteins with druggable pockets have been discovered to interact with RhoA. We stipulated
that small molecules that bind to these druggable targets will promote axonal regeneration and recovery to a
similar or greater extent than direct inhibition of RhoA activity. To identify such compounds we pursued a unique
approach that consisted of structure-based computational docking of large chemical libraries to druggable targets
that interact with RhoA. We tested the top 50-100 compounds for their effect on neurite outgrowth and axonal
regeneration. One compound, RLA-47, inhibited in vitro neurite outgrowth and axonal regeneration. The
compound also showed substantial axon crossings in an animal model of spinal cord injury. Our central
hypothesis is that RLA-47 and its derivatives will promote axonal regeneration and recovery following spinal cord
injury. Our preliminary data puts us in a strong position to test our hypothesis. In our first aim, we propose to
design and synthesize derivatives of RLA-47 that will be tested in our neurite outgrowth and axonal regeneration
in vitro assays. The most promising candidates will be explored in our in vivo hemisection model of spinal cord
injury. In our second aim, we propose to develop RLA-47 derivatives with suitable pharmacokinetics and blood-
brain permeability that promote axonal regeneration in vivo. We also test the most promising compounds using
a more clinically relevant contusion model of spinal cord injury. We will use a standard chemical biology strategy
of affinity purification and mass spectrometry to uncover targets of RLA-47 and its derivatives. Along with RNA
sequencing, these studies will provide deeper insight into the mechanism of action of compounds. We expect
1-2 derivatives of RLA-47 to exhibit superior pharmacokinetics, brain permeability and efficacy. These
compounds will lead to investigational new drug filing that we expect will eventually lead to candidates that can
be explored in clinical trials either alone, or in combination with other therapies to promote regeneration and
recovery in spinal cord injury patients.

## Key facts

- **NIH application ID:** 10293587
- **Project number:** 5I01BX005188-02
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Samy Meroueh
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293587

## Citation

> US National Institutes of Health, RePORTER application 10293587, Small Molecules to Promote Regeneration and Recovery Following Spinal Cord Injury (5I01BX005188-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10293587. Licensed CC0.

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