PHD Inhibitor Vadadustat: The First Drug Therapy for Triosephosphate Isomerase Deficiency

Background/Objectives: Triosephosphate isomerase deficiency (TPI Df) is an ultra-rare autosomal recessive glycolytic disorder characterized by symptoms of hemolytic anemia, progressive neuromuscular dysfunction, and early mortality. The TPI1E105D mutation (TPI1 variant p.Glu105Asp) accounts for most cases, though TPI Df can also arise from other pathogenic variants, including compound heterozygous TPI1 variants such as TPI1R5G/f.s (p.(Arg5Gly)/p.(Ile151Serfs*3)). TPI1R5G/f.s presents with an atypical predominantly neurological phenotype characterized by severe dystonia, dysarthria, basal ganglia involvement, and cognitive impairment, without hemolytic anemia or peripheral neuromuscular disease. Regardless of the causative allele(s), reduced mutant TPI protein stability is the central pathogenic mechanism. We previously hypothesized that pharmacological inhibition of prolyl hydroxylase domain (PHD) enzymes, leading to hypoxia-inducible factor (HIF) stabilization, could increase TPI protein levels and attenuate disease severity.