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

Abstract Alcohol Use DisorderAUDis a chronic condition characterized by compulsive alcohol useloss of control over alcohol useand a negative emotional state when not using alcoholwith such use associated with a range of medicalpsychologicalsocialeconomicand personal problemsAUD is global and prevalentin a survey of overadults in the USAUD had amonth prevalence ofaffecting overmillion adults in the US inThe total economic cost in the US is estimated at $billion per yearAUD often goes untreatedpossibly partly due to the lack of adequate treatment optionsit is estimated that andltof US adults who meet the criteria for AUD seek help or treatmentand that similarly low percentages of those treated for AUD receive pharmacotherapyThere exists a large unmet medical need for effective treatments for AUDThere are three FDA approved medications for AUDdisulfiramoral and long acting injectable naltrexoneand acamprosatehowevermany individuals show limited or no response to thesewith poor compliance a factorDicerna is developing an siRNA to silence ALDHgene expression in liverDCR ALDHas a treatment for AUDDCR ALDHhas been fully optimizedand significantly reduces ALDHin vitro and in liver in intact mice and monkeysand demonstrated efficacy in a mouse binge drinking modelThe goal of this project is to advance DCR ALDHthrough INDenabling studies and early clinical testing for AUDIn this Uwe propose five Aims in Phase Iand three Aims in Phase IIIn SBIR Phase Iwe propose to synthesize non cGMP drug substance for exploratory studiesdevelop the relevant assays for downstream activitiesand perform dose range finding PK PD studies and look at biodistribution in mice and NHPsThese activities should lead to a pre IND meeting with FDAIn SBIR Phase IIwe will synthesize the cGMP lot of drug and conduct IND enabling toxicology studies in mouse and NHPFollowing success with these aimswe will commence a Phase I clinical trialOur primary outcome measure is safetyas evaluated by occurrence of adverse events or serious adverse eventsOur secondary outcome measures include drug PK PDand effect of drug on acetaldehyde levels after ethanol administrationDicerna anticipates having a significant impact on the treatment of AUD by having a long actingspecific drug with few to no side effects that will improve patient compliance Narrative Alcohol Use DisorderAUDis a chronic condition characterized by compulsive alcohol useand is associated with a range of medicalpsychologicalsocialeconomicand personal problemsAUD affected overmillion adults in the US inDicerna is developing a long acting drug that will silence the ALDHgeneleading to unpleasant effects after drinkingto deter compulsive alcohol use