Rapid Haplotyping procedure for determining the response of patients to DCA

 描述(申请人提供)：二氯乙酸酯(DCA)在治疗儿童和成人的几种罕见和常见的危及生命的疾病方面具有治疗潜力。这些疾病包括先天性丙酮酸脱氢酶复合体缺乏症(PDCD)、肺动脉高压(PAH)、糖尿病、心脏病、癌症和其他已被研究为治疗药物的疾病。然而，DCA具有潜在的神经毒性，限制了其临床应用。Medosome Biotec，LLC(MBT)及其在佛罗里达大学(UF)的研究伙伴认为，存在一个巨大的市场，可以开发和商业化GSTZ1基因分型试剂盒，用于使用DCA治疗PDCD和其他由DCA受益的疾病。Medosome Biotec及其佛罗里达大学的研究伙伴(Peter Stacpoole博士和Taimour Langaee博士)使用焦磷酸测序技术识别了人类GSTZ1的单倍型变异，这些变异导致DCA的血浆清除率不同。Stacpoole博士发现了DCA的药效学特性，并带头将其用作FDA宣布的罕见疾病孤儿产品。慢性DCA的唯一临床限制性不良反应是可逆的 周围神经病。Stacpoole博士已经证明，这种毒性可以通过基于GSTZ1单倍型状态的个性化剂量的DCA来预防。这些有希望的研究为中心SBIR假说奠定了基础，即基于GSTZ1单倍型剂量的DCA有可能为PDCD和其他DCA可能有益的疾病提供安全有效的治疗。因此，这项SBIR第一阶段赠款的目标将是开发和应用一种用于确定GSTZ1单倍型的原型商业试剂盒，医生可以使用该试剂盒对DCA进行个性化剂量治疗，以治疗PDCD和其他对DCA应用有反应的疾病。该建议的具体目的将是：1)开发基于单核苷酸多态(SNPs)的GSTZ1单倍型分析的标准操作程序(SOP)和用于从潜在患者收集样本和健康信息的配套试剂盒；2)使用针对特定目标1开发的试剂盒和分析程序，识别和分析健康成年人群中GSTZ1单倍型的频率；以及3)基于GSTZ1单倍型分析，通过在特定目标2中确定的DCA代谢缓慢或快速的受试者的子集中测定DCA的血浆药代动力学(PK)，确定GSTZ1单倍型分析的准确性和有效性。

 DESCRIPTION (provided by applicant): Dichloroacetate (DCA) has therapeutic potential in treating several rare and common life-threatening diseases of children and adults. These include congenital pyruvate dehydrogenase complex deficiency (PDCD), pulmonary arterial hypertension (PAH), diabetes, heart disease, cancer and other diseases in which it has been investigated as a therapeutic. However, DCA is potentially neurotoxic, limiting its clinical use. Medosome Biotec, LLC (MBT) and its research partners at the University of Florida (UF), believe a significant market exists to develop and commercialize a kit for GSTZ1 genotyping for use in administering DCA for the treatment of PDCD and other disorders benefitted by DCA. Medosome Biotec and its research partners at University of Florida (Drs. Peter Stacpoole and Taimour Langaee) have used pyrosequencing techniques to identify haplotype variations in human GSTZ1 that confer variable rates of plasma clearance of DCA. Dr. Stacpoole discovered the pharmacodynamic properties of DCA and has led in its use as an FDA-declared Orphan Product for rare diseases. The only clinically limiting adverse effect of chronic DCA is reversible peripheral neuropathy. Dr. Stacpoole has shown that this toxicity may be prevented by personalized dosing of DCA, based on GSTZ1 haplotype status. These promising studies serve as the basis for the central SBIR hypothesis that GSTZ1 haplotype-based dosing of DCA has the potential to provide safe and effective treatment for PDCD and other diseases for which DCA may be beneficial. Accordingly, the goal of this SBIR Phase I grant will be to develop and apply a prototype commercial kit for determining GSTZ1 haplotypes that can be used by physicians for personalized dosing of DCA for the treatment of PDCD and other diseases responsive to DCA administration. The Specific Aims of the proposal will be to: 1) Develop standard operating procedures (SOPs) for GSTZ1 haplotype analysis based on Single Nucleotide Polymorphisms (SNPs) and a companion kit for collecting samples and health information from prospective patients; 2) Identify and analyze the frequency of GSTZ1 haplotypes in a healthy adult population, using the kit and analytic procedures developed in Specific Aim 1 and, 3) Establish the accuracy and validity of the GSTZ1 haplotype analysis by determining the plasma pharmacokinetics (PK) of DCA in a subset of subjects identified in Specific Aim 2 who are predicted to be slow or fast DCA metabolizers, based on GSTZ1 haplotype analysis.