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A rapid and portable test for home monitoring of phenylalanine levels by patients with phenylketonuria using a blood glucose meter

使用血糖仪在家监测苯丙酮尿症患者苯丙氨酸水平的快速便携式测试

基本信息

批准号：
9346910
负责人：
Tian Lan
金额：
$ 22.35万
依托单位：
GLUCOSENTIENT, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9346910
关键词：
Address Adult Affect Age Amino Acids Ataxia Biological Assay Blood Blood - brain barrier anatomy Blood Glucose Blood Glucose Self-Monitoring Blood specimen Brain Brain Injuries Characteristics Child Child Development Childhood Classical phenylketonuria Clinic Clinical Color Custom Data Detection Development Developmental Delay Disorders Devices Diabetes Mellitus Diagnosis Diet Effectiveness Electrodes Ensure Enzymes Exposure to Family Feedback Fetus Food Foundations Glucose Growth Health Home environment Human Impairment Infant Laboratories Life Measures Medical Medical Device Metabolic Diseases Methods Microcephaly Monitor NADH Neurocognitive Neurologic Newborn Infant Nutrient Optics Outcome Oxidoreductase Patient Monitoring Patients Performance Phase Phenylalanine Phenylalanine Hydroxylase Phenylketonurias Physicians Pregnancy Pregnant Women Procedures Production Protein-Restricted Diet Proteins Reaction Time Reagent Recovery Reporting Research Risk Sampling Seizures Serum Signal Transduction Small Business Innovation Research Grant Stabilizing Agents Stream Symptoms System Technology Test Result Testing Time Tyrosine Validation Variant Visit Work assay development base cofactor commercialization congenital heart disorder cost design detector diabetic glucose monitor improved innovation instrument meter monitoring device neurotoxic point of care portability prototype research and development scale up sensor

项目摘要

Project Summary/Abstract Phenylketonuria (PKU) is a serious inborn metabolic disorder affecting 1 out of every 15,000 children born in the U.S. annually. Characteristic effect of PKU is the impaired capability of the body to convert the amino acid phenylalanine (Phe) to tyrosine and, as a result, Phe level is elevated in the blood stream. While Phe is required for normal growth and brain development, excess Phe leads brain damage and ultimately severe intellectual impairment. The effects of prolonged exposure to Phe is much more pronounced during childhood and pregnancy, resulting in growth retardation and neurological impairment in children, development delay, microcephaly and congenital heart disease in fetuses. Therefore, patients with PKU need carefully control and monitoring of their blood Phe level for their whole lives, especially for infants, children and pregnant women. To control blood Phe levels, a specially designed low Phe diet, which is devoid of protein-containing food, must be followed. Since Phe diet are difficult to follow and prolonged exposure to elevated Phe as well as frequent fluctuation of blood Phe impacts normal growth and brain development, blood Phe levels are routinely monitored for patients with PKU. However, monitoring blood Phe today requires long turn-around time, since blood sample needs to be first collected via a blood drawn or on filter card, then analyzed in a clinical laboratory using costly and sophisticated instrument. Hence, many PKU patients can only maintain a suboptimal blood Phe levels, even they are willing to make dietary adjustment. Therefore, home Phe monitoring providing with immediate test result is imperative to achieve better health outcomes and to avoid neurocognitive issues. Although methods have been reported for monitoring Phe at home, most of them rely on optical detection that is vulnerable to interferences from colored species in clinical samples, or electrochemical detection that uses sophisticated assay methods or highly modified electrochemical detectors, limiting their commercial potentials. Based on this compelling need and our recent discovery that many commercially available Blood Glucose Meters (BGMs) can measure levels of NADH, a cofactor in many enzymatic assays, we propose to repurpose the BGM widely used by diabetics for PKU patients to monitor blood Phe levels. We have developed a technology that allows the direct use of existing glucose test strips for quantification of Phe, via an enzyme phenylalanine dehydrogenase that generates NADH in the presence of Phe. Furthermore, we have developed a customized meter to improve the NADH sensitivity while still using existing glucose test strips. In this Phase I project, we will focus on demonstrating the feasibility by developing a BGM based Phe assay followed by sensor strip development. By leveraging today’s BGM platform, we can drastically reduce the time and cost associated with medical device R&D and scale up production, while delivering an easy-to-use and affordable solution for PKU patients to monitor their Phe levels rapidly at home or at any point of care setting.

项目总结/摘要苯丙酮尿症（PKU）是一种严重的先天性代谢紊乱，每15，000名新生儿中就有1名患此病在美国每年。PKU的特征效应是身体转化氨基酸的能力受损苯丙氨酸（Phe）转化为酪氨酸，结果，血流中的Phe水平升高。虽然Phe是必需的对于正常的生长和大脑发育，过量的苯丙氨酸会导致大脑损伤，最终导致严重的智力障碍。损伤长期接触苯丙氨酸的影响在儿童时期更为明显，怀孕，导致儿童生长迟缓和神经损伤，发育迟缓，胎儿的小头畸形和先天性心脏病。因此，PKU患者需要仔细控制，监测他们的血液Phe水平为他们的整个生命，特别是对婴儿，儿童和孕妇。为了控制血液中的苯丙氨酸水平，一种特别设计的低苯丙氨酸饮食，不含含蛋白质的食物，必须遵循。由于苯丙氨酸饮食难以遵循，长期暴露于升高的苯丙氨酸，血液Phe的频繁波动会影响正常生长和大脑发育，血液Phe水平通常是监测PKU患者。然而，今天监测血液Phe需要很长的周转时间，因为首先需要通过抽血或过滤卡采集血样，然后在临床实验室进行分析使用昂贵和复杂的仪器。因此，许多PKU患者只能维持次优的血Phe 水平，甚至他们愿意做出饮食调整。因此，家庭Phe监测提供即时测试结果对于实现更好的健康结果和避免神经认知问题至关重要。尽管已经报道了用于在家中监测Phe的方法，但是它们中的大多数依赖于光学检测，易受临床样品中有色物质的干扰，或使用复杂的分析方法或高度改进的电化学检测器，限制了它们的商业潜力。基于这种迫切的需求和我们最近的发现，许多市售的血糖血糖仪（BGM）可以测量NADH的水平，这是许多酶测定中的辅因子，我们建议重新使用糖尿病患者广泛使用的BGM用于PKU患者监测血液Phe水平。我们开发了一种技术允许直接使用现有的葡萄糖测试条，通过苯丙氨酸酶来定量Phe 在Phe存在下产生NADH的脱氢酶。此外，我们还开发了定制的血糖仪，以提高NADH的灵敏度，同时仍然使用现有的葡萄糖试纸。在第一阶段，我们将重点是通过开发基于BGM的Phe检测试剂盒，然后开发传感器条来证明可行性发展通过利用当今的BGM平台，我们可以大幅减少与医疗器械研发和规模化生产，同时为北大提供易于使用且价格合理的解决方案患者在家中或任何护理点快速监测其Phe水平。