Iminosugars for treatment of antitrypsin deficiency

DESCRIPTION (Applicant's Abstract): Alpha-1 antitrypsin (al-AT) deficiency is a relatively common genetic disorder. A subgroup of deficient individuals develops chronic liver disease and hepatocellular carcinoma. The liver injury is caused by the toxic effect of the mutant al-ATZ molecule that is retained in the ER of liver cells. The deficient state is also characterized by susceptibility to emphysema due to uninhibited proteolytic damage to the lung. We have recently established genetically engineered cell and transgenic mouse models of al-AT deficiency for studies of potential pharmacotherapeutic strategies. In the model cell system we have found that an iminosugar, castanospermine, alters carbohydrate side chain trimming and, surprisingly, mediates an increase in secretion of al-ATZ. Because mutant a1-ATZ partially retains functional activity and because clinical studies have suggested that only partial correction is needed for prevention of liver and lung injury in al-AT deficiency, iminosugars constitute excellent candidates for chemoprophylaxis in al-AT deficiency. In this proposed Phase I STIR program, we will combine the expertise of the Perlmutter lab at Washington University in studying al-AT deficiency with the expertise of Synergy Pharmaceuticals in development of iminosugars for therapeutic purposes to identify a lead compound for testing in human patients as a part of a subsequent planned Phase II STIR program. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE