Rapid Haplotyping procedure for determining the response of patients to DCA

 描述（由申请人提供）：二氯乙酸盐（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。这些包括先天性丙酮酸脱氢酶复合物缺乏症（PDCD）、肺动脉高压（PAH）、糖尿病、心脏病、癌症和其他疾病，其中它已被研究作为治疗剂。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）的研究合作伙伴认为，存在一个重要的市场来开发和商业化GSTZ 1基因分型试剂盒，用于给予DCA治疗PDCD和其他受益于DCA的疾病。Medosome Biotec及其在佛罗里达大学的研究合作伙伴（Peter Stacpoole和Taimour Langaee博士）使用焦磷酸测序技术鉴定了人GSTZ 1的单倍型变异，这些变异赋予DCA的血浆清除率可变。Stacpoole博士发现了DCA的药效学特性，并将其作为FDA宣布的罕见病孤儿药使用。慢性DCA的唯一临床限制性不良反应是可逆的 周围神经病变Stacpoole博士已经表明，这种毒性可以通过基于GSTZ 1单倍型状态的DCA个性化给药来预防。这些有希望的研究作为中心SBIR假设的基础，即基于GSTZ 1单体型的DCA给药有可能为PDCD和其他DCA可能有益的疾病提供安全有效的治疗。因此，SBIR第一阶段资助的目标是开发和应用一种用于确定GSTZ 1单倍型的原型商业试剂盒，该试剂盒可由医生用于DCA的个性化给药，用于治疗PDCD和其他对DCA给药有反应的疾病。该提案的具体目标是：1）制定基于单核苷酸多态性（SNP）的GSTZ 1单倍型分析的标准操作程序（SOP）和配套试剂盒，用于从潜在患者中收集样本和健康信息; 2）使用Specific Aim 1中开发的试剂盒和分析程序，鉴定和分析健康成人群体中GSTZ 1单倍型的频率，3）基于GSTZ 1单倍型分析，通过确定特定目标2中鉴定的被预测为缓慢或快速DCA代谢者的受试者子集中DCA的血浆药代动力学（PK），建立GSTZ 1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.