# Development of an ALDH2-Targeting RNAi Therapeutic for Alcohol Use Disorders

> **NIH NIH U44** · DICERNA PHARMACEUTICALS, INC. · 2021 · $1,500,000

## Abstract

Abstract
Alcohol Use Disorder (AUD) is a chronic condition characterized by compulsive alcohol use, loss of
control over alcohol use, and a negative emotional state when not using alcohol, with such use
associated with a range of medical, psychological, social, economic, and personal problems. AUD is
global and prevalent; in a survey of over 36,000 adults in the US, AUD had a 12-month prevalence of
13.9%, affecting over 44 million adults in the US in 2015. The total economic cost in the US is
estimated at $250-300 billion per year. AUD often goes untreated, possibly partly due to the lack of
adequate treatment options; it is estimated that <10% of US adults who meet the criteria for AUD
seek help or treatment, and that similarly low percentages of those treated for AUD receive
pharmacotherapy. There exists a large unmet medical need for effective treatments for AUD. There
are three FDA-approved medications for AUD: disulfiram, oral and long-acting injectable naltrexone,
and acamprosate; however, many individuals show limited or no response to these, with poor
compliance a factor. Dicerna is developing an siRNA to silence ALDH2 gene expression in liver
(DCR-ALDH2) as a treatment for AUD. DCR-ALDH2 has been fully optimized, and significantly
reduces ALDH2 in vitro and in liver in intact mice and monkeys, and demonstrated efficacy in a
mouse binge drinking model. The goal of this project is to advance DCR-ALDH2 through IND-
enabling studies and early clinical testing for AUD. In this U44, we propose five Aims in Phase I, and
three Aims in Phase II. In SBIR Phase I, we propose to synthesize non-cGMP drug substance for
exploratory studies, develop the relevant assays for downstream activities, and perform dose-range
finding PK/PD studies and look at biodistribution in mice and NHPs. These activities should lead to a
pre-IND meeting with FDA. In SBIR Phase II, we will synthesize the cGMP lot of drug and conduct
IND-enabling toxicology studies in mouse and NHP. Following success with these aims, we will
commence a Phase I clinical trial. Our primary outcome measure is safety, as evaluated by
occurrence of adverse events or serious adverse events. Our secondary outcome measures include
drug PK/PD, and effect of drug on acetaldehyde levels after ethanol administration. Dicerna
anticipates having a significant impact on the treatment of AUD by having a long-acting, specific drug
with few to no side effects that will improve patient compliance.

## Key facts

- **NIH application ID:** 10241554
- **Project number:** 5U44AA027404-04
- **Recipient organization:** DICERNA PHARMACEUTICALS, INC.
- **Principal Investigator:** Bob D. Brown
- **Activity code:** U44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,500,000
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241554

## Citation

> US National Institutes of Health, RePORTER application 10241554, Development of an ALDH2-Targeting RNAi Therapeutic for Alcohol Use Disorders (5U44AA027404-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10241554. Licensed CC0.

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