Oxidation-resistant Anti-protease Therapy

AbstractLEXEO TherapeuticsLLCis an early stage biotechnology company focused on using gene therapy technologies to protect vulnerable organs from oxidant stressLEXthest LEXEO productis ast in classnext generation gene therapy treatment for alphaantitrypsinAATdeficiencyan autosomal recessive hereditary disorder associated with low serum levels of AATAATSERPINAakDa serine antiprotease produced by the liverprotects the lung from proteolytic enzymes released by inflammatory cellsIn AAT deficiencythe lung is vulnerable to destruction by proteolytic enzymes released by inflammatory cells that degrade the lungresulting in emphysemaAAT deficiency is currently treated with weekly infusions of AAT purified from pooled human plasmaGene therapy for AAT deficiency holds the promise that a single administration will generate sufficient amounts of AAT to protect the lung on a persistent basisobviating weekly AAT protein therapyFirst generation gene therapy strategies are under development to treat AAT deficiency using adenoassociated virusAAVgene transfer vectors to deliver the human AAT coding sequence in vivo by various routesThe Achilles heel of these strategies is the sensitivity of the AAT molecule to oxidantsThe active site of human AAT includes Metwith acontribution by MetWhen oxidizede gby cigarette smokeinflammatory cell productsambient pollutionAAT is rendered ineffective and cannot inhibit neutrophil elastaseits primary targetLEXdesigned as an AAV vector coding for an elastase inhibitingoxidation resistant human AATsolves this problem with substitution at Metand or Metwith Val or Leu to render the AAT molecule oxidation resistantyet maintaining its function as an anti elastaseThis is a Fast Track application with the goal of being clinical trial ready withinyrSuccessful completion of these aims will make LEXEO attractive for biotechpharma and or venture investmentPhase IAimUsing the normal MAAAT coding sequence as a baseassess combinations of MetLeu and Val at positionsandto determine the optimal neutrophil elastase inhibitingoxidation resistant form of AAT to use in LEXPhase IAimDetermine that intrapleural administration of LEXto experimental animals results in persistenthigh levels of oxidation resistant human AAT in serum and lung epithelial lining fluidPhase IAimHave a preIND meeting with the FDA regarding the LEXdevelopment planPhase IIAimProduce and validate GMP clinical grade LEXand demonstrate in experimental animals it is safe to use in a human trialPhase IIAimDevelop and validate the assays to be used in the clinical studySubmit to the FDA an IND permitting initiation of a phase I clinical study of LEXfor AAT deficiency NarrativeLEXEO Therapeutics is developing ast in classnext generationgene therapy strategy to treat alphaantitrypsinAATdeficiencya hereditary disorder associated with early development of emphysemaThe deliverable of this Fast Track application is an FDA approved investigational new drug application permitting initiation of a phase I clinical trial to treat AAT deficiency with a single administration of LEXan adeno associated gene transfer vector coding for a non oxidizable form of AAT