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 TPI1^E105D 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 TPI1^R5G/f.s (p.(Arg5Gly)/p.(Ile151Serfs*3)). TPI1^R5G/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. Methods: We evaluated PHD inhibitors, including vadadustat and roxadustat, in patient-derived TPI1^E105D/E105D fibroblasts and Tpi1^E105D/E105D mouse models. In addition, vadadustat was administered off-label as compassionate therapy to a TPI Df patient. Studies assessed TPI protein levels, enzymatic activity, hematological parameters, and clinical outcomes. Results: In FB303 patient fibroblasts, vadadustat (100 μM) and roxadustat (100 μM) increased TPI protein levels by ~45% and ~68%, and TPI enzymatic activity by ~191% and ~258%, respectively. In Tpi1^E105D/E105D mice, vadadustat significantly increased TPI levels in liver, kidney, and muscle tissues along with partial improvement in neuromuscular function, as assessed by rotarod performance. Supported by these findings, compassionate off-label administration with vadadustat/Vafseo was initiated in a single TPI1^R5G/f.s. patient. Treatment was associated with a progressive increase in residual TPI enzymatic activity, clinical stabilization, and meaningful neurological improvement, predominantly affecting left-sided motor function, including improved upper-limb dexterity, recovery of functional grasping, and complete resolution of myoclonic-like movements. Conclusions: This report provides the first in vivo evidence that pharmacological stabilization of mutant TPI1 protein may represent a novel therapeutic strategy for TPI deficiency. Furthermore, the findings establish PHD inhibitors, such as vadadustat, as excellent candidates for disease-modifying therapy of TPI Df warranting further development and clinical investigation.