A New and Unique Approach to Potentially Improving Treatment Outcomes for People With Alcohol Use Disorder (AUD)
DCR-AUD is a GalXC™ RNAi candidate that Dicerna is developing for the treatment of alcohol use disorder (AUD). Designed to silence ALDH2 mRNA expression selectively in the liver, DCR-AUD has been shown to induce long-lasting liver-specific ALDH2 mRNA knockdown in nonclinical studies.
Dicerna initiated a randomized, double-blind, placebo-controlled Phase 1 trial in the third quarter of 2021 to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of single –ascending doses of DCR-AUD over a 24-week observation period in healthy volunteers. The trial will formally assess the interaction between DCR-AUD treatment and alcohol consumption and confirm ALDH2 knockdown using pharmacodynamic biomarkers.
What is ALDH2?
Alcohol metabolism occurs predominantly in the liver in a two-step process in which alcohol is first converted to acetaldehyde via alcohol dehydrogenase (ADH) and then to acetic acid by ALDH2. Inhibiting the ALDH2 enzyme can result in unpleasant symptoms that result from increased acetaldehyde when alcohol is consumed but not fully metabolized. The severity of symptoms in this situation is proportional to both the degree of ALDH2 enzyme inhibition (e.g., partial vs. total) and the amount of alcohol consumed.
Some people (primarily those of Asian ancestry) are born with naturally occurring mutations in one or both gene copies that encode the ALDH2 enzyme. In people with ALDH2 mutations, even small amounts of alcohol consumption can result in uncomfortable physiological effects like flushing, headache, nausea, and other typical “hangover” effects that occur soon after drinking. These effects are thought to be the reason why people with ALDH2 mutations are observed to naturally have a low lifetime prevalence of AUD.
DCR-AUD was developed using our GalXC RNAi technology to specifically knock down ALDH2 protein expression in the liver, with the intent to provide a protective “guardrail” against harmful levels of alcohol use in individuals seeking treatment for AUD. DCR-AUD was designed by Dicerna based on the human genetic data that suggested knocking down ALDH2 mRNA in patients with AUD may help them in a way similar to how naturally occurring ALDH2 mutations appear to be protective of AUD. By specifically targeting ALDH2 mRNA in the liver, DCR-AUD acts directly where the majority of alcohol metabolism occurs.
References
World Health Organization. Global status report on alcohol and health 2018. https://www.paho.org/hq/index.php?option=com_docman&view=download&slug=who-s-global-status-report-on-alcohol-and-health-2018-1&Itemid=270&lang=en. Accessed Nov. 23, 2021.
V. Vasiliou, D.R. Petersen. ALDH2 Alcoholism and Disease. Comprehensive Toxicology. 2010; 4: 131-147.
