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OXALATE BIODEGRADING PROBIOTIC FOR KIDNEY STONE PREVENTION - PROJECT SUMMARY/ABSTRACT THIS SBIR PHASE II PROJECT FOLLOWS UP ON A HIGHLY SUCCESSFUL PHASE I PROJECT, WHERE WE INITIATED THE DEVELOPMENT OF A NEW AND INNOVATIVE PROBIOTIC STRAIN DESIGNED FOR THE PREVENTION OF KIDNEY STONES. THIS NOVEL PROBIOTIC STRAIN HAS AN OPTIMIZED ABILITY TO BIODEGRADE OXALIC ACID. ABOUT 75% OF KIDNEY STONES CONSIST OF CALCIUM OXALATE (CAOX), AND THE ROOT CAUSE OF CAOX STONES IS AN EXCESSIVE URINARY OXALATE LEVELS. THERE ARE FEW TOOLS AVAILABLE TO PREVENT CAOX STONES, AND NONE ADDRESS THIS ROOT CAUSE. CURRENT KIDNEY STONE PREVENTION APPROACHES RELY MOSTLY ON DIETARY MODIFICATIONS, AN LEAN HEAVILY INCREASING FLUID INTAKE. HOWEVER, ADHERENCE RATES ARE COMMONLY BELOW 50%. AVOIDING OXALATE-RICH FOODS IS ALSO RECOMMENDED TO LIMIT CALCIUM OXALATE STONE GROWTH, BUT AGAIN, ADHERENCE RATES ARE LOW, AND A LOW OXALATE DIET IS DIFFICULT TO FOLLOW. THERE ARE FEW TOOLS AVAILABLE BEYOND DIETARY ADJUSTMENTS: ALKALINIZING AGENTS SUCH AS POTASSIUM CITRATE CAN REDUCE STONE RECURRENCE, BUT CAN BE SURPRISINGLY COSTLY AND OFTEN CAUSE GI DISTRESS. THIAZIDE DIURETICS INCREASE URINARY VOLUME AND REDUCE URINARY SUPERSATURATION, BUT THEY COME WITH FREQUENT, POTENTIALLY LIFE-THREATENING ADVERSE EFFECTS SUCH AS HYPOKALEMIA. IN CONTRAST, OUR PROBIOTIC IS A SAFE, COST-EFFECTIVE, INNOVATIVE AND PROMISING STRATEGY FOR ELIMINATING OXALIC ACID BEFORE IT CAN BE ABSORBED IN THE SMALL INTESTINE, WITH THE GOAL BEING A REDUCTION IN OXALIC ACID LEVELS IN URINE. THE MAIN IMPACT OF THIS PROJECT WILL BE THE DEVELOPMENT OF AN ACCESSIBLE, AFFORDABLE AND SAFE TOOL THAT DOES NOT HAVE SIDE EFFECTS SEEN WITH AVAILABLE TREATMENT OPTIONS. THE PROPOSED SBIR PHASE II PROJECT IS DESIGNED TO OVERCOME REMAINING STEPS THAT NEED TO BE COMPLETED BEFORE COMMERCIALIZATION OF OUR PROPOSED INNOVATION. THROUGH PHASE II AIMS 1-4 WE WILL COMPLETE CRITICAL ACTIVITIES, INCLUDING SCALE-UP, CONFIRMATION OF EFFICACY IN A RAT MODEL OF KIDNEY STONES, AND DEMONSTRATING SAFETY AND TOLERABILITY IN ORDER TO OBTAIN GENERALLY RECOGNIZED AS SAFE (GRAS) AFFIRMATION. THE SEVERE PHYSICAL PAIN AND SUFFERING, THE SERIOUS ADVERSE PSYCHOLOGICAL DISTRESS, AND THE VERY SERIOUS ADVERSE ECONOMIC IMPACT CAUSED BY KIDNEY STONES UNDERSCORES THE NEED TO EXPLORE NEW AND INNOVATIVE PREVENTION APPROACHES. ANTICIPATED RISES IN THE PREVALENCE OF KIDNEY STONES AND HYPEROXALURIA, ALONG WITH THE LIMITATIONS OF CURRENT TREATMENTS STRONGLY EMPHASIZE THE SOCIETAL DEMAND FOR A HYPEROXALURIA TREATMENT THAT IS NOT ONLY ACCESSIBLE AND AFFORDABLE BUT ALSO SAFE.

CONSTITUTIVE OXALATE-BIODEGRADING BACILLUS SUBTILIS FOR KIDNEY STONES - PROJECT SUMMARY / ABSTRACT KIDNEY STONES (NEPHROLITHIASIS) ARE AN EXTREMELY PAINFUL AND DEBILITATING CONDITION. ABOUT 12% OF PEOPLE WILL EXPERIENCE KIDNEY STONES IN THEIR LIFETIME, AND ABOUT 70% OF THOSE WILL HAVE RECURRENCES. THE ECONOMIC BURDEN OF KIDNEY STONES IS ESTIMATED TO EXCEED $5 BILLION PER YEAR IN THE USA ALONE. EACH YEAR, OVER 3 MILLION WORKDAYS ARE LOST IN THE USA DUE TO KIDNEY STONES. 75% OF KIDNEY STONES CONSIST OF CALCIUM OXALATE (CAOX), AND ARE CAUSED BY EXCESSIVE URINARY OXALATE LEVELS. UNFORTUNATELY, CURRENT TREATMENT OPTIONS ALL HAVE SERIOUS DRAWBACKS. A LOW OXALATE DIET IS ROUTINELY RECOMMENDED FOR CAOX STONE PATIENTS, BUT IS NOT VERY EFFECTIVE BY ITSELF. ALKALINIZING AGENTS SUCH AS POTASSIUM CITRATE CAN REDUCE STONE RECURRENCE, BUT ARE COSTLY AND OFTEN CAUSE GI DISTRESS. THIAZIDE DIURETICS COME WITH FREQUENT, POTENTIALLY LIFE-THREATENING ADVERSE EFFECTS SUCH AS HYPOKALEMIA. THUS, THERE REMAINS A STRONG NEED FOR THE DEVELOPMENT OF NEW KIDNEY STONE TREATMENT OPTIONS THAT ARE BOTH SAFE AND EFFECTIVE. WE PROPOSE TO DEVELOP AND TEST A NEW KIDNEY STONE TREATMENT CONSISTING OF A NOVEL BACILLUS SUBTILIS STRAIN THAT OVEREXPRESSES ENDOGENOUS OXALATE BIODEGRADING ENZYMES. AS BACTERIA STAY IN THE GUT, THE SPECTRUM OF POTENTIAL SIDE EFFECTS IS MASSIVELY REDUCED AS COMPARED TO SMALL MOLECULE DRUGS. THUS, OUR INNOVATIVE APPROACH IS DESIGNED TO RESULT IN AN AFFORDABLE, SAFE, AND BROADLY EFFECTIVE KIDNEY STONE TREATMENT OPTION. IN THIS PHASE I SBIR PROJECT, WE WILL DEVELOP NEW BACILLUS SUBTILIS STRAINS ENGINEERED TO BIODEGRADE OXALATE. WE WILL PRODUCE AND TEST DIFFERENT STRAINS TO OPTIMIZE OXALATE BIODEGRADATION CAPACITY. AS WE WILL CHROMOSOMALLY OVEREXPRESS ENDOGENOUS ENZYMES IN A SPORE-FORMING BACTERIUM, OUR APPROACH AVOIDS KEY DRAWBACKS OF PREVIOUSLY DEVELOPED OXALATE- DEGRADING MICROBES. FINALLY, WE WILL DETERMINE IF THE BEST PERFORMING ENGINEERED STRAIN CAN EFFECTIVELY REDUCE URINE OXALATE LEVELS IN A RELEVANT RAT MODEL.

SBIR PHASE I: ENGINEERING PROBIOTIC YEAST TO TREAT HYPERURICEMIA AND GOUT