Personalized dosing of dichloroacetate for the treatment of rare and common diseases

丙酮酸脱氢酶复合体缺乏(PDCD)是一种罕见的线粒体能量衰竭疾病。 这严重缩短了受影响儿童的预期寿命。PDCD的治疗仍然是一个严重的问题， 未满足，挑战。从来没有对PDCD进行任何干预的对照试验；因此，没有 针对受影响患者的有效治疗方法。二氯乙酸酯(DCA)代表了PDCD的第一个靶向治疗，通过 刺激所有组织中残留的PDC活性，包括中枢神经系统(CNS)。基于这两个 DCA治疗线粒体疾病的对照试验和开放标记研究，Medosome Biotec，LLC(MBT)和 它在佛罗里达大学(UF)的研究伙伴(Peter Stacpoole博士和Taimour Langaee博士，PD/PIS 阶段I)确定数据足够令人信服，以证明DCA的关键阶段3试验在 UF的Stacpoole博士和哥伦比亚大学的J.L.P.Thompson博士是PD/PI。在……里面 响应这些充满希望的研究和广泛的潜在商业市场，Medosome Biotec，LLC (MBT)及其在UF的研究伙伴开发了一个中心STTR假设，即GSTZ1基于单倍型 DCA的剂量有可能为PDCD和其他疾病提供安全有效的治疗 其中DCA可能是有益的。该团队提出了一个STTR快速通道来测试这一点。第一阶段：制定 GSTZ1单倍型分析程序(称为卤型鉴定程序或HIP)，可以 由医生用于个性化剂量的DCA。第一阶段的具体目标：1)建立准确性和 DCA在受试者的血浆药代动力学(PK)测定对GSTZ1单倍型分析的有效性 根据GSTZ1单倍型，在特定目标2中确定哪些人被预测为慢或快的DCA代谢者 分析。第二阶段：使用新程序对PDCD患者进行准确的基因分型和剂量分层 第三阶段试验。该团队将通过实现以下第二阶段的具体目标来测试这些假设：1) 根据FDA的指导方针进行关键的3期试验，这可能会导致该机构批准 PDCD的DCA，使用第一阶段开发的程序提供个性化的、基于遗传学的剂量 提高慢性DCA治疗的安全性；以及2)将试剂盒和分析程序商业化以供使用 在PDCD和其他适合DCA治疗的疾病中。

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure in which the life of expectancy of affected children is severely truncated. Treatment of PDCD remains a serious, unmet, challenge. There has never been a controlled trial of any intervention for PDCD; thus, there is no proven therapy for affected patients. Dichloroacetate (DCA) represents the first targeted therapy for PDCD by stimulating residual PDC activity in all tissues, including the central nervous system (CNS). Based on both controlled trials and open label studies of DCA in mitochondrial diseases, Medosome Biotec, LLC (MBT) and its research partners at the University of Florida (UF) (Drs. Peter Stacpoole and Taimour Langaee, PD/PIs for Phase I) determined the data were sufficiently compelling to justify a pivotal phase 3 trial of DCA in this disease, for which Dr. Stacpoole at UF and Dr. J.L.P. Thompson at Columbia University are PD/PIs. In response to these promising studies and extensive potential commercial market, Medosome Biotec, LLC (MBT) and its research partners at UF have developed a central STTR hypothesis that GSTZ1 haplotypebased dosing of DCA has the potential to provide safe and effective treatment for PDCD and other diseases for which DCA may be beneficial. The team proposes a STTR Fast Track to test this. Phase I: Develop a procedure for GSTZ1 haplotypes analysis (referred to as Halotype Identification Procedure or HIP) that can be used by physicians for personalized dosing of DCA. Phase I Specific Aim: 1) Establish the accuracy and validity of the GSTZ1 haplotype analysis by determining the plasma pharmacokinetics (PK) of DCA in subjects identified in Specific Aim 2 who are predicted to be slow or fast DCA metabolizers, based on GSTZ1 haplotype analysis. Phase II: Use the new procedure to accurately genotype and dose-stratify PDCD patients for the Phase 3 trial. The team will test these hypotheses by accomplishing the following Phase II Specific Aims: 1) Conduct a pivotal Phase 3 trial, consistent with FDA guidelines, that could lead to the agency’s approval of DCA for PDCD, using the procedure developed during Phase I to provide personalized, genetics-based dosing to improve the safety of chronic DCA treatment; and 2) Commercialize the kit and analytic procedures for use in PDCD and other diseases amenable to DCA treatment.