Project Grant R41DK138551

NOVEL ADIPOSE TARGETED GENE THERAPY FOR LIPODYSTROPHY - PROJECT SUMMARY LIPODYSTROPHY INCLUDES A HETEROGENEOUS GROUP OF DISORDERS THAT ARE CHARACTERIZED BY ABNORMAL OR DEGENERATIVE CONDITIONS OF THE ADIPOSE TISSUE. THIS RARE AND OFTEN UNDERDIAGNOSED CONDITION CAN BE PARTIAL/LOCALIZED OR GENERALIZED AND IS GENERALLY ASSOCIATED WITH METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE, DIABETES, HYPERGLYCEMIA, HYPERLIPIDEMIA, AND OTHER SEVERE CONDITIONS. LIPODYSTROPHY CAN BE CONGENITAL OR ACQUIRED AND CAN OFTEN LEAD TO DEADLY CONSEQUENCES DUE TO LIVER, KIDNEY, AND CARDIAC COMPLICATIONS. ALL FORMS OF LIPODYSTROPHY HAVE SEVERE INSULIN RESISTANCE AND VERY LOW LEPTIN LEVELS. CURRENTLY, LEPTIN REPLACEMENT USING METRELEPTIN IS THE ONLY TREATMENT OF LIPODYSTROPHY. HOWEVER, METRELEPTIN INJECTIONS AT A DOSE OF ONCE OR TWICE A DAY COST AN AVERAGE OF $565,000 PER PATIENT/YEAR AND CAN HAVE ADVERSE SIDE EFFECTS. ZVELT THERAPEUTICS IS DEVELOPING A SAFE, EFFICIENT, AND COST-EFFECTIVE THERAPY FOR THE TREATMENT OF LIPODYSTROPHY. THIS THERAPY IS MEDIATED BY RECOMBINANT ADENO-ASSOCIATED VIRUS (RAAV) VECTORS THAT OFFER LONG-LASTING TRANSGENIC EXPRESSION AND LOW IMMUNOGENICITY. TYPICALLY, WHEN AAV THERAPIES ARE DELIVERED SYSTEMICALLY, THE VAST MAJORITY OF AAVS ARE SEQUESTERED IN THE LIVER, WITH LITTLE EXPRESSION IN TARGET TISSUES. THIS EFFECT CAUSES A NARROW THERAPEUTIC WINDOW, AS SYSTEMIC AAV MUST BE DOSED NEAR TOXIC LEVELS TO ATTAIN THERAPEUTIC BENEFITS. TO OVERCOME THESE CHALLENGES, ZVELT WILL USE A NOVEL ENGINEERED AAV SEROTYPE REC2 THAT PREFERENTIALLY TARGETS FAT, COUPLED WITH A DUAL CASSETTE PLATFORM THAT MINIMIZES TRANSGENE EXPRESSION IN THE LIVER. ZVELT THERAPEUTICS HAS ALREADY ESTABLISHED THE PROOF OF EFFICACY OF THE REC2/DUAL CASSETTE VECTOR CONTAINING THE LEPTIN GENE (REC2-LEPTIN) FOR CORRECTING LEPTIN DEFICIENCY, OBESITY, AND METABOLIC SYNDROMES IN MOUSE MODELS. ZVELT'S PLATFORM HAS BEEN DEMONSTRATED TO EXPRESS IN THE TARGETED ADIPOSE TISSUE WHILE RESTRICTING OFF-TARGET EXPRESSION IN THE LIVER IN THE MOUSE MODEL. IN THIS STTR PHASE I PROJECT, WE WILL PERFORM DOSE-FINDING AND SAFETY ANALYSES OF REC2-LEPTIN IN RELEVANT LIPODYSTROPHY MOUSE MODELS TOWARDS VALIDATION OF THIS INNOVATION FOR THE EFFECTIVE TREATMENT OF LIPODYSTROPHY. IN PHASE II, WE WILL ADDRESS KEY TECHNICAL ASPECTS OF PRODUCT DEVELOPMENT AND SAFETY AND EFFICACY STUDIES IN LARGER ANIMAL MODELS TO OBTAIN ESSENTIAL DATA TO SUPPORT IND APPLICATION. THIS WILL PAVE THE WAY FOR A FIRST-IN- HUMAN CLINICAL STUDY TO COLLECT EVIDENCE ON THE SAFETY AND EFFICACY OF THE TREATMENT FOR LIPODYSTROPHY.