Gene Therapy to Prevent Esophageal Cancer Associated with Aldehyde Dehydrogenase Deficiency

AbstractLEXEO TherapeuticsLLCis an early stage biotechnology company focused on using in vivo gene therapy technologies to treat disorders of unmet medical needLEXEO is developing an in vivo gene therapy strategy as a preventative therapy to protect individuals with aldehyde dehydrogenaseALDHdeficiency from the high risk for esophageal cancerAs the next step in the development paththe goal of this Phase I STTR is to demonstrate that a single intravenous administration of LEXa serotype rhadeno associated virus coding for human ALDHwill suppress the chronic ethanol ingestion associated development of cancer related DNA damage and adducts in the esophagus of ALDHdeficient miceALDHdeficiencya common hereditary disorder affectingmillion peopleof the world populationhas a high prevalence in people of East Asian backgroundALDHis a key enzyme for ethanol metabolismmutations that reduce the oxidizing ability of the enzyme result in systemic accumulation of toxic acetaldehydeWith ethanol ingestionthe dysfunction of ALDHis linked to theAsian flush syndromewith facial flushingheadachenauseadizziness and cardiac palpitationsMost importantlyaffected individuals have atofold increased risk of cancer of the oral cavitypharynxlarynxand esophagusThe combination of cigarette smoking and alcohol consumption with the ALDHgenotype is associated with one of the highest known cancer risksodds ratioand ayr earlier onset of esophageal carcinomaAt presentthere is no preventative therapy for the increased risk for esophageal cancer in this populationThe long term expression and impact of the gene therapy will be assessed inmouse models of ALDHdeficiency chronically exposed to ethanol to induce acetaldehyde accumulationesophageal DNA damage and adductsWe hypothesize that LEXtherapy will prevent the accumulation of cancer risk associated DNA damage and adducts induced by chronic ethanol ingestionThe demonstration that LEXwill prevent esophageal DNA damage and adduct accumulation in these mouse models will be sufficient preclinical efficacy data to initiate an STTR phaseproduct development to move toward an issued IND to carry out initial clinical studiesWe propose the following aimAimTo evaluate the hypothesis that LEXAAVrhhALDHtherapy will prevent ethanol induced DNA damage and adduct formation in the esophagus in ALDHand ALDH EKmiceSerum levels of acetaldehyde will be monitoredMarkers of DNA damage and acetaldehyde induced DNA adducts will be assessed in esophageal tissuesMilestoneTo demonstrate that at doses relevant to humansLEXwill reduce esophageal DNA damage and adduct formation in both mouse models by andgtNarrativeAldehyde dehydrogenaseALDHdeficiencya hereditary disorder common in individuals of East Asian descentis associated with a high incidence of aerodigestive cancers in affected individuals with chronic alcohol consumptionThe focus of this Phase I STTR is to develop LEXan adeno associated gene transfer vector coding for ALDHto prevent the high risk of esophageal cancer associated with ALDHdeficiency