Project Grant R41AR086039

HLA GENE EDITING IN THE TREATMENT OF RHEUMATOID ARTHRITIS - PROJECT SUMMARY RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE THAT CAUSES CHRONIC INFLAMMATION, PAIN AND LOSS OF FUNCTION IN VARIOUS JOINTS. IT AFFECTS ~0.46% OF THE WORLD POPULATION AND ~0.6% (2 MILLION) OF THE US POPULATION, AND SIGNIFICANTLY ADDS TO THE US HEALTHCARE COSTS. TREATMENT OF RA REQUIRES A COMPLEX SYSTEMATIC APPROACH WITH FREQUENT MONITORING OF DISEASE ACTIVITY AND MEDICATION SIDE EFFECTS TO DETERMINE THE OPTIMAL THERAPEUTIC REGIMEN FOR EACH PATIENT. CURRENTLY, THE TREATMENT INVOLVES LIFETIME THERAPY WITH IMMUNOSUPPRESSIVE DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (DMARDS). DESPITE A WIDE RANGE OF TREATMENT OPTIONS, WITH THE INTRODUCTION OF TNF INHIBITORS AND OTHER TARGETED THERAPIES IN MOST PATIENTS, PATIENTS STILL HAVE A SHORTENED LIFE EXPECTANCY (~10 YEARS), REPORT REDUCED QUALITY OF LIFE AND ~10% OF PATIENTS STILL HAVE PROGRESSIVE DISEASE WITH CURRENT TREATMENT OPTIONS (REFRACTORY RA). THUS, THERE REMAINS A SIGNIFICANT POPULATION OF REFRACTORY RA PATIENTS IN DESPERATE NEED OF AN EFFECTIVE THERAPEUTIC. MANY REFRACTORY PATIENTS, DUE TO LACK OF AN EFFECTIVE STRATEGY, PROGRESS MORE RAPIDLY TO SEVERE JOINT DISEASE. RHEUMAGEN AIMS TO ADDRESS CURRENT GAPS BY DEVELOPING RG0401, AN EX VIVO AUTOLOGOUS CD34+ HEMATOPOIETIC PROGENITOR AND STEM CELL (HPC)-BASED GENE THERAPY IN WHICH THE DRB1*04:01 RA-INDUCING ALLELE IS REPLACED BY A RESISTANT ALLELE, DIFFERING BY A SINGLE AMINO ACID (DRB1*04:01K71E). RG0401 IS DESIGNED AS A ONE-TIME THERAPY, WHERE GENE EDITED HPCS WILL GENERATE IMMUNE CELLS THAT CAN NO LONGER ACTIVATE THE ARTHRITOGENIC T CELLS THAT CAUSE JOINT DISEASE IN RA. RHEUMAGEN AND CLINIMMUNE'S TEAM HAVE DEMONSTRATED PRECLINICAL EFFICACY USING A TRANSGENIC MOUSE MODEL AND HAVE ESTABLISHED THAT THE EDIT IS NOT ALLOREACTIVE IN VIVO. GENE EDITING WILL BE PERFORMED WITH A CRISPR SGRNA SPECIFIC FOR DRB1*04:01 AND AAV6 DELIVERED REPAIR DNA CONTAINING THE THERAPEUTIC GENE AND A GENE MARKER TO ALLOW SELECTION OF GENE EDITED CELLS. IN THIS STTR PHASE I, RHEUMAGEN WILL (1) OPTIMIZE AND DEFINE THE BEST GENE EDITING STRATEGY IN HUMAN GENE-EDITED HPCS AND CONFIRM OF ALLELE SPECIFICITY WITHIN THE DRB1 LOCUS VIA SEQUENCING, (2) PERFORM STUDIES TO DETERMINE THE LEVEL OF DRB1*04:01K71E CHIMERISM REQUIRED FOR EFFICACY. THE SUCCESSFUL COMPLETION OF THIS STTR PHASE I PROJECT WILL BE FOLLOWED BY PHASE II IN WHICH PRECLINICAL SAFETY STUDIES ON THE GENE-EDITED HUMAN HPCS TO ESTABLISH GENOMIC EFFECTS, STEMNESS, POTENCY, PURITY AND SAFETY OF THE GENE EDITED HPCS. THE DATA FROM THESE STUDIES WILL BE USED TO SUPPORT THE PRECLINICAL AND CLINICAL DEVELOPMENT PLANS FOR AN IND SUBMISSION.