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.
Public Health Relevance Statement: Project Narrative Almost 80% of kidney stones are caused by excessive oxalate levels. Theraneutrics proposes to develop a complementary kidney stone treatment consisting of probiotic bacteria engineered to break down oxalate. Because probiotics stay in the gut and don't enter the circulation, our treatment will be a safe, affordable and effective treatment option.
Project Terms: Oral Administration; Oral Drug Administration; intraoral drug delivery; Bacillus subtilis; B subtilis; B. subtilis; Bacteria; Biodegradation; Blood Circulation; Bloodstream; Circulation; Western Blotting; Immunoblotting; Western Immunoblotting; protein blotting; Calcium Oxalate; calcium salt Ethanedioic acid; Diet; diets; Thiazide Diuretics; Benzothiadiazine Diuretics; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Enzymes; Enzyme Gene; Government; Health; Human; Modern Man; Hypokalemia; Hypopotassemia; In Vitro; Intestines; Intestinal; bowel; Investments; Kidney Calculi; Kidney Stones; Renal Calculi; Renal Stone; Laws; Metabolism; Intermediary Metabolism; Metabolic Processes; Microbiology; Persons; Oxalates; Painful; Pain; Patents; Legal patent; Patients; well-being; wellbeing; Personal Satisfaction; Production; Common Rat Strains; Rat; Rats Mammals; Rattus; Recurrent; Recurrence; Development and Research; R & D; R&D; research and development; Safety; Self Determination; Spores; Reproduction spores; Testing; Toxicology; Urine; Urine Urinary System; Water; Hydrogen Oxide; Oxalate decarboxylase; oxalate carboxy-lyase; Health Care Costs; Health Costs; Healthcare Costs; potassium citrate; base; dosage; improved; Area; Phase; Evaluation; Distress; diet supplement; nutritional supplement; dietary supplements; root; Plant Roots; Letters; Life; Renal lithiasis; Nephrolithiasis; Clinic; Probiotics; experience; basicity; alkalinity; novel; Position; Positioning Attribute; Modeling; response; Adverse effects; small molecule; Address; Dose; Data; Economic Burden; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; follow-up; Active Follow-up; active followup; follow up; followed up; followup; urinary; Development; developmental; metabolic engineering; cost; design; designing; innovation; innovate; innovative; Microbe; commercialization; overexpression; overexpress; effective therapy; effective treatment; in vivo evaluation; in vivo testing; side effect
