# Administrative Core

> **NIH NIH U19** · MARINE BIOLOGICAL LABORATORY · 2021 · $666,478

## Abstract

Chronic pain is a leading cause of disability, affecting about one-third of adults worldwide, with a prevalence
greater than heart disease, cancer, and diabetes combined. Misuse and abuse of opiates have led to a
nationwide addiction and overdose crisis. Thus, there is an urgent need for alternative, non-addictive analgesics.
Non-selective voltage-gated sodium channel (Nav) blockers are among existing non-addictive FDA-approved
drugs which can sometimes provide symptomatic relief for patients. However, their utility is limited by CNS and
cardiac side effects. Genetic and functional studies of human pain disorders and animal models of pain have
validated NaV1.7, a voltage-gated Na Channel that is preferentially expressed in peripheral neurons, as an
attractive target for therapy. Isoform-selective Nav blockers, however, are difficult to generate and those that
have been generated are rapidly cleared from the body, limiting their effectiveness. Alternative approaches are
needed. We propose a novel, non-addictive approach to treat chronic pain by editing the messages that encode
NaV1.7 in order to alter its electrophysiological properties. By changing a single lysine codon to arginine in the
ion selectivity filter, the channel will go from being Na+ selective to both Na+ and K+ selective, effectively creating
a counter-current shunt that will dampen excitability.
Site-Directed RNA Editing (SDRE) refers to novel mechanisms to generate programmed edits within RNAs. It
relies on the ADAR (Adenosine Deaminase that Acts on RNA) enzymes, which are endogenously expressed in
human cells, including sensory neurons. Directed by a guide RNA (gRNA), SDRE systems convert precisely
selected adenosines to inosine, a translational mimic for guanosine, which can recode specific amino acids. For
use as an analgesic, editing mRNA is preferable to DNA because it is transient, thus limiting potential off-target
effects, including malignant transformations and ADARs are endogenous while enzymes for DNA manipulation
(e.g. Cas proteins) are not, thus SDRE will not be as immunogenic. Compared to small molecule channel
blockers, SDRE can be more specific, because it relies on Watson-Crick base-pairing of gRNAs for targeting,
and its effects are likely longer lasting because they will remain as long as the edited channels are expressed.
We propose to use SDRE to edit NaV1.7 K1395R to render the channel permeable to both Na+ and K+. The
purpose of the Administrative Core is to develop an administrative structure to support the goals of the project.
This includes committees and guidelines for keeping track of scientific milestones, resolving conflicts in
intellectual property and other areas, overseeing budgets and finances, and ensuring accurate and timely
reporting to the NIH.

## Key facts

- **NIH application ID:** 10398387
- **Project number:** 1U19NS126038-01
- **Recipient organization:** MARINE BIOLOGICAL LABORATORY
- **Principal Investigator:** JOSHUA J.C. ROSENTHAL
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $666,478
- **Award type:** 1
- **Project period:** 2021-09-23 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10398387

## Citation

> US National Institutes of Health, RePORTER application 10398387, Administrative Core (1U19NS126038-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10398387. Licensed CC0.

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