Rapid Haplotyping procedure for determining the response of patients to DCA

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 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.