Constitutive oxalate-biodegrading Bacillus subtilis for kidney stones

用于肾结石的组成型草酸盐生物降解枯草芽孢杆菌

• 批准号: 10484663
• 负责人: Christoph Geisler
• 金额: $ 25.93万
• 依托单位: UNLOCKED LABS INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484663
• 关键词: Address; Adverse effects; Area; Bacillus subtilis; Bacteria; Biodegradation; Blood Circulation; Calcium Oxalate; Clinic; Data; Development; Diet; Distress; Dose; Economic Burden; Engineering; Enzymes; Evaluation; Government; Health; Health Care Costs; Human; Hypokalemia; In Vitro; Intestines; Investments; Kidney Calculi; Laws; Legal patent; Letters; Life; Metabolism; Microbe; Microbiology; Modeling; Nephrolithiasis; Oral Administration; Oxalate decarboxylase; Oxalates; Pain; Patients; Personal Satisfaction; Persons; Pharmaceutical Preparations; Phase; Plant Roots; Positioning Attribute; Probiotics; Production; Rattus; Recurrence; Reproduction spores; Safety; Self Determination; Small Business Innovation Research Grant; Testing; Thiazide Diuretics; Toxicology; Urine; Water; Western Blotting; alkalinity; base; commercialization; cost; design; dietary supplements; dosage; effective therapy; experience; follow-up; improved; in vivo; in vivo evaluation; innovation; metabolic engineering; novel; overexpression; potassium citrate; research and development; response; side effect; small molecule; urinary

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.

项目摘要 /摘要 肾结石（肾结石病）是一种极其痛苦和令人衰弱的状况。关于 12％的人一生都会经历肾结石，其中约有70％的人会 复发。肾结石的经济负担估计每年超过50亿美元 仅在美国。每年，由于肾结石，在美国损失了超过300万个工作日。 75％的肾结石由草酸钙（CAOX）组成，是由过度尿引起的 草酸盐水平。 不幸的是，当前的治疗方案都有严重的缺点。低氧饮食是 通常建议使用Caox Stone患者，但本身不是很有效。碱化 诸如柠檬酸钾的特工可以减少石材复发，但代价高昂，通常会导致 gi困扰。噻嗪类利尿剂具有频繁的，潜在的威胁生命的不良反应 例如低钾血症。因此，仍然需要发展新肾脏 既安全有效又有效的石材处理选择。 我们建议开发和测试一种由小说组成的新肾结石治疗 枯草芽孢杆菌过度表达内源性草酸盐生物降解酶。作为 细菌留在肠道中，潜在副作用的光谱大大降低了 与小分子药物相比。因此，我们的创新方法旨在导致 负担得起，安全且广泛有效的肾结石治疗选择。 在这个阶段I SBIR项目中，我们将开发新的枯草枯草枯草菌菌株 生物降解草酸盐。我们将产生和测试不同的菌株以优化草酸盐 生物降解能力。因为我们将在A中染色体过表达的内源性酶 形成孢子的细菌，我们的方法避免了先前开发的草酸盐的关键缺点 降解微生物。最后，我们将确定表现最好的工程菌株是否可以 有效地降低相关大鼠模型中的草酸盐水平。