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Trial Begins Testing RNA Therapy for Alcohol Disorder

Pouring a drink

(Duc Quang Tran, Pixabay)

28 Sept. 2021. A clinical trial is underway testing a therapy that silences genes to create reactions in people with alcohol use disorder to help them stop drinking. Dicerna Pharmaceuticals Inc. in Lexington, Massachusetts is conducting the early-stage study testing its treatment candidate for alcohol use disorder code-named DCR-AUD with healthy volunteers.

Alcohol use disorder, commonly called alcoholism, is a condition where people cannot control their drinking despite known adverse consequences to their health, work, family, and social life. One result of alcohol use disorder, or AUD, is changes in brain functioning that perpetuates the condition, and makes people with the disorder susceptible to relapse. Survey data from 2019 cited by National Institute on Alcohol Use and Alcoholism show 14.1 million adults in the U.S. with alcohol use disorder, as well as some 414,000 adolescents age 12 to 17. Current treatments for alcohol use disorder include support groups, behavioral therapies, and some medications.

Dicerna Pharmaceuticals is a biotechnology company that develops therapies blocking actions of disease-causing genes using a process known as RNA interference. Ribonucleic acid or RNA is produced by genes with instructions to cells coded from DNA to synthesize proteins. With RNA interference, or RNAi, those instructions are interrupted, preventing production of proteins from disease-causing genes, while limiting effects on other genes, RNA, and protein synthesis.

Produce uncomfortable physiological reactions when drinking

Dicerna’s technology known as GalXC silences disease-causing genes in the liver. The company’s process adds N-acetylgalactosamine, a sugar molecule, to Dicer enzymes that process double-stranded RNA. Dicerna says these engineered enzymes prevent messenger RNA, the part of RNA molecules with protein synthesis instructions, from reaching the target cells. The company says GalXC treatments are stable and can be delivered as injections under the skin, while targeting cells in the liver. Moreover, says Dicerna, the process is flexible enough to be applied to a range of target genes, addressing a number of disease types including viral infectious diseases, chronic liver disorders, cardiovascular conditions, and some rare diseases.

Dicerna created DCR-AUD to silence expression of messenger RNA from aldehyde dehydrogenase 2 or ALDH2 genes in the liver. Mutations in ALDH2 genes block production of enzymes that result in unpleasant physiological reactions when exposed to alcohol, causing people with these mutations to stop drinking. The drug disulfiram addresses ALDH2 enzymes and is approved by FDA to treat alcohol use disorder. But disulfiram is associated with serious adverse effects, including hepatitis and neurological reactions, limiting its use in some people.

DCR-AUD is designed to silence ALDH2 expression in much the same way as those mutations, thus encouraging people with alcohol use disorder to limit their alcohol consumption. Dicerna envisions DCR-AUD as a supplemental treatment to behavioral and support-group therapies. “We designed DCR-AUD,” says Dicerna chief medical officer Shreeram Aradhye in a company statement, “leveraging our GalXC RNAi technology to serve as a potential therapeutic that offers real-time physiological feedback to complement the evidence-based psychosocial treatments used to help individuals with AUD.”

The clinical trial is enrolling 36 healthy volunteers testing varying doses of DCR-AUD. Participants are randomly assigned to receive a dose of DCR-AUD or a placebo, then observed closely for six hours for adverse effects. Following this initial observation, participants are followed-up weekly for 24 weeks, with the study team looking primarily for incidence and severity of adverse effects. Researchers are also tracking participants’ vital signs and chemical activity of DCR-AUD in the blood.

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