RARE DISEASE
Triose phosphate-isomerase deficiency
Triose phosphate-isomerase deficiency
Triose phosphate-isomerase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Triose Phosphate-Isomerase Deficiency (TPI Deficiency)
TPI deficiency is a rare autosomal recessive disorder caused by mutations in the TPI1 gene, leading to impaired glycolysis. It presents with hemolytic anemia from infancy, progressive neurodegeneration (dystonia, tremors, hypotonia), cardiomyopathy, and recurrent infections. Severe cases often result in respiratory failure or fatal cardiomyopathy by early childhood, though rare survivors into adulthood exist [1][13][18]. Diagnosis involves reduced TPI enzyme activity and genetic testing [16][18].
Burden
High mortality: Most patients die by age 5–10 due to respiratory/cardiac failure [1][18].
Severe disability: Progressive neuromuscular decline necessitates lifelong multidisciplinary care [13][18].
Limited treatment efficacy: Chronic transfusions risk iron overload, while HSCT carries significant morbidity [3][13].
Therapies
Supportive care: Regular blood transfusions, splenectomy for hemolysis, and infection management [3][18].
Hematopoietic stem cell transplant (HSCT): Curative potential demonstrated in isolated cases, improving anemia and possibly delaying neurodegeneration [3][7].
Experimental approaches: Enzyme replacement therapy and small molecules targeting metabolic pathways remain under investigation [10][16].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
36 drug discovery papers about Triose phosphate-isomerase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
36 drug discovery papers about Triose phosphate-isomerase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-08 | Biophysical and biochemical studies support PHD inhibitor development as a TPI deficiency therapy.
Triosephosphate isomerase deficiency (TPI Df) is an ultra-rare genetic enzymopathy. Previously, the TPIR5G allele was found to cause TPI Df when combined with a null allele. Here, we report a 1.15 Å TPIR5G crystal structure providing insight into disease pathogenesis. Previously, we conducted a high-throughput screen that identified TPI-inducing compounds, including predicted hypoxia inducible factor (HIF) inducers. We have investigated repurposing HIF activators/prolyl hydroxylase domain inhibitors (PHDIs) as TPI Df treatments. We tested the efficacy of these compounds in cells from individuals with TPI Df. Our results demonstrate that PHDIs increase TPI protein levels and TPI activity, suggesting they should be further developed for TPI Df. RNA-sequencing and reverse transcription quantitative polymerase chain reaction (RT-qPCR) experiments were performed to analyze PHDI-induced gene expression changes. We discovered that chronic PHDI treatment results in HIF1-antisense 2 (HIF1-AS2) activation, which operates as a negative feedback loop in the HIF pathway. These results demonstrate that repurposing PHDIs for TPI Df is a promising avenue of research deserving further investigation. Our results also suggest that PHDIs may also benefit dozens of other heritable disease conditions if treatment avoids HIF1-AS2 activation.
2026-02-16 | Familial Dystonia Due to Homozygous TPI1 c.718G>A (p.Glu240Lys): A Three-Sibling Case Series Including Two Treated with Deep Brain Stimulation of the Globus Pallidus Internus.
Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive disorder caused by mutations in the TPI1 gene, typically presenting with anemia, infections, and neurological decline. We report three siblings with a homozygous c.718G>A (p.Glu240Lys) variant presenting predominantly with dystonia. Clinical and genetic evaluations were performed in three affected siblings from a consanguineous Turkish family. Neurological examinations, imaging, and surgical outcomes were reviewed. All three siblings exhibited truncal and axial dystonia with orthopedic deformities but without anemia or cardiac involvement. Cognitive functions were preserved. Two underwent bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS), resulting in partial yet clinically meaningful improvement in posture and gait. The third sibling received orthopedic interventions. Notably, one homozygous sibling remained asymptomatic, highlighting incomplete penetrance. This is the first genetically confirmed report of TPI1 -associated dystonia treated with GPi-DBS. Our findings expand the clinical spectrum of TPI deficiency, showing a neurologically predominant phenotype without hematologic manifestations. The observed variability suggests the role of modifier factors, and GPi-DBS may provide symptomatic benefit in severe cases.
2025-10-29 | Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1R5G.
Background/Objectives: Triosephosphate Isomerase (TPI) is a glycolytic enzyme known to be associated with TPI deficiency, a severe form of childhood-onset glycolytic enzymopathy associated with hemolytic anemia, neuromuscular impairment and early death. Most often the disease results from the common TPI1E105D mutation, which can be either homozygous or compound heterozygous with another allele. Methods: We purified TPIR5G protein, studied mutant protein biochemistry, established and characterized TPIR5G/f.s.patient cells, and investigated newly identified compounds for their efficacy in vitro using Western blot and TPI activity assays. Results: We identified novel TPI1 alleles that result in TPI Deficiency with an atypical presentation lacking anemia and with more slowly developing neurologic and locomotor impairment. The patient was found to be compound heterozygous with a missense mutation resulting in an R5G amino acid substitution and a frameshift mutation that is a predicted null allele. To better understand disease pathogenesis in this patient, we expressed and purified the TPIR5G human protein and studied it biochemically in addition to studying TPIR5G/f.s.patient cells. We discovered that purified TPIR5G protein has wildtype activity with modestly increased dimer stability. We also discovered that steady-state TPI protein levels were markedly reduced, suggesting that the instability of the mutant protein underlies disease pathogenesis. We tested compounds recently identified in a screen for novel TPI Df therapies for their efficacy in TPIR5G/f.s.patient cells. All three compounds significantly increased TPI protein levels in patient cells. As expected, since the mutant protein retains essentially wild type activity, the increase in TPI protein levels also resulted in a significant increase in TPI activity. Conclusions: These results establish TPIR5G as a TPI Df allele, demonstrate that reduced stability of the mutant protein underlies pathogenesis akin to other disease-causing alleles, and suggest that recently discovered developing therapies will likely function broadly and should be developed as potential TPI Df therapies.
2025-09-22 | Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report.
Background and Clinical Significance: Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive metabolic disorder caused by a pathogenic variant in the TPI1 gene. It is characterised by chronic haemolytic anaemia, progressive neuromuscular dysfunction, and reduced life expectancy. Patients typically present with symptoms in the first few months of life, including muscle weakness, ataxia, and recurrent respiratory infections. Diagnosis is confirmed by genetic testing, and management is generally symptomatic as no treatment is available. Case Presentation: We describe the case of an infant diagnosed with TPI deficiency in the context of haemolytic anaemia with progressive neurological deterioration and respiratory failure. Conclusions: This case illustrates the complexity of the disease and highlights the importance of early diagnosis and contributes to the limited literature by providing a detailed clinical description and highlighting the diagnostic challenges associated with this condition. Beyond its clinical relevance, this report emphasises the potential role of personalised medicine in the management of TPI deficiency. Early identification of specific genotypes may inform prognosis and guide individualised supportive strategies. As knowledge of the molecular underpinnings of TPI deficiency expands, opportunities may emerge for targeted therapeutic approaches tailored to patient-specific characteristics.
2025-09-19 | Discovery and validation of small molecule stabilizers of mutant triose phosphate isomerase (TPI) as potential lead candidates for TPI deficiency.
Triosephosphate Isomerase deficiency (TPI-Df) is a devastating untreatable childhood metabolic disease resulting in anemia, severe locomotor impairment, and premature death. Numerous single amino acid substitutions in TPI are pathogenic and result in rapidly progressing multisystem disease. Importantly, all known pathogenic TPI-Df mutations result in a protein that retains function, and pathogenesis is known to result from decreased steady state levels of the functioning protein. There are no small molecule therapies for TPI-Df; current treatments are limited to symptomatic support and dietary interventions. We reasoned that a phenotypic screen was most appropriate to capture agents that stabilize mutant TPI and developed a human cellular TPI-Df assay based on a cellular model of the "common" TPIE105D mutant protein fused with a GFP and a fluorescent ROS biosensor. The assay was implemented for high-content, high-throughput imaging, optimized to full HTS standards, and used to screen a 2,560 compound pilot library and the 220,700 compound NIH MLSMR compound collection to identify candidate compounds for development into small molecule TPI-Df therapies. Hits were validated in dose-response, TPI-Df patient cells, and various orthogonal assays. Limited SAR revealed three promising compound series, which were evaluated for potential mechanisms of action. The lead series had previously been identified as inducers of HIF1 alpha, spawning a novel hypothesis that HIF1 alpha activation might be a potential avenue to treat TPI-Df patients. A lead molecule was moved into preliminary mouse studies to evaluate pharmacokinetics and tissue distribution and was shown to be moderately brain-penetrant. The lead compound is now positioned for target identification studies and efficacy testing in vivo TPI Df models, including a newly validated mouse model.
2026-04-08 | Biophysical and biochemical studies support PHD inhibitor development as a TPI deficiency therapy.
Triosephosphate isomerase deficiency (TPI Df) is an ultra-rare genetic enzymopathy. Previously, the TPIR5G allele was found to cause TPI Df when combined with a null allele. Here, we report a 1.15 Å TPIR5G crystal structure providing insight into disease pathogenesis. Previously, we conducted a high-throughput screen that identified TPI-inducing compounds, including predicted hypoxia inducible factor (HIF) inducers. We have investigated repurposing HIF activators/prolyl hydroxylase domain inhibitors (PHDIs) as TPI Df treatments. We tested the efficacy of these compounds in cells from individuals with TPI Df. Our results demonstrate that PHDIs increase TPI protein levels and TPI activity, suggesting they should be further developed for TPI Df. RNA-sequencing and reverse transcription quantitative polymerase chain reaction (RT-qPCR) experiments were performed to analyze PHDI-induced gene expression changes. We discovered that chronic PHDI treatment results in HIF1-antisense 2 (HIF1-AS2) activation, which operates as a negative feedback loop in the HIF pathway. These results demonstrate that repurposing PHDIs for TPI Df is a promising avenue of research deserving further investigation. Our results also suggest that PHDIs may also benefit dozens of other heritable disease conditions if treatment avoids HIF1-AS2 activation.
2026-02-16 | Familial Dystonia Due to Homozygous TPI1 c.718G>A (p.Glu240Lys): A Three-Sibling Case Series Including Two Treated with Deep Brain Stimulation of the Globus Pallidus Internus.
Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive disorder caused by mutations in the TPI1 gene, typically presenting with anemia, infections, and neurological decline. We report three siblings with a homozygous c.718G>A (p.Glu240Lys) variant presenting predominantly with dystonia. Clinical and genetic evaluations were performed in three affected siblings from a consanguineous Turkish family. Neurological examinations, imaging, and surgical outcomes were reviewed. All three siblings exhibited truncal and axial dystonia with orthopedic deformities but without anemia or cardiac involvement. Cognitive functions were preserved. Two underwent bilateral deep brain stimulation of the globus pallidus internus (GPi-DBS), resulting in partial yet clinically meaningful improvement in posture and gait. The third sibling received orthopedic interventions. Notably, one homozygous sibling remained asymptomatic, highlighting incomplete penetrance. This is the first genetically confirmed report of TPI1 -associated dystonia treated with GPi-DBS. Our findings expand the clinical spectrum of TPI deficiency, showing a neurologically predominant phenotype without hematologic manifestations. The observed variability suggests the role of modifier factors, and GPi-DBS may provide symptomatic benefit in severe cases.
2025-10-29 | Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1R5G.
Background/Objectives: Triosephosphate Isomerase (TPI) is a glycolytic enzyme known to be associated with TPI deficiency, a severe form of childhood-onset glycolytic enzymopathy associated with hemolytic anemia, neuromuscular impairment and early death. Most often the disease results from the common TPI1E105D mutation, which can be either homozygous or compound heterozygous with another allele. Methods: We purified TPIR5G protein, studied mutant protein biochemistry, established and characterized TPIR5G/f.s.patient cells, and investigated newly identified compounds for their efficacy in vitro using Western blot and TPI activity assays. Results: We identified novel TPI1 alleles that result in TPI Deficiency with an atypical presentation lacking anemia and with more slowly developing neurologic and locomotor impairment. The patient was found to be compound heterozygous with a missense mutation resulting in an R5G amino acid substitution and a frameshift mutation that is a predicted null allele. To better understand disease pathogenesis in this patient, we expressed and purified the TPIR5G human protein and studied it biochemically in addition to studying TPIR5G/f.s.patient cells. We discovered that purified TPIR5G protein has wildtype activity with modestly increased dimer stability. We also discovered that steady-state TPI protein levels were markedly reduced, suggesting that the instability of the mutant protein underlies disease pathogenesis. We tested compounds recently identified in a screen for novel TPI Df therapies for their efficacy in TPIR5G/f.s.patient cells. All three compounds significantly increased TPI protein levels in patient cells. As expected, since the mutant protein retains essentially wild type activity, the increase in TPI protein levels also resulted in a significant increase in TPI activity. Conclusions: These results establish TPIR5G as a TPI Df allele, demonstrate that reduced stability of the mutant protein underlies pathogenesis akin to other disease-causing alleles, and suggest that recently discovered developing therapies will likely function broadly and should be developed as potential TPI Df therapies.
2025-09-22 | Challenges in the Diagnosis and Management of Triosephosphate Isomerase Deficiency: A Case Report.
Background and Clinical Significance: Triosephosphate isomerase (TPI) deficiency is a rare autosomal recessive metabolic disorder caused by a pathogenic variant in the TPI1 gene. It is characterised by chronic haemolytic anaemia, progressive neuromuscular dysfunction, and reduced life expectancy. Patients typically present with symptoms in the first few months of life, including muscle weakness, ataxia, and recurrent respiratory infections. Diagnosis is confirmed by genetic testing, and management is generally symptomatic as no treatment is available. Case Presentation: We describe the case of an infant diagnosed with TPI deficiency in the context of haemolytic anaemia with progressive neurological deterioration and respiratory failure. Conclusions: This case illustrates the complexity of the disease and highlights the importance of early diagnosis and contributes to the limited literature by providing a detailed clinical description and highlighting the diagnostic challenges associated with this condition. Beyond its clinical relevance, this report emphasises the potential role of personalised medicine in the management of TPI deficiency. Early identification of specific genotypes may inform prognosis and guide individualised supportive strategies. As knowledge of the molecular underpinnings of TPI deficiency expands, opportunities may emerge for targeted therapeutic approaches tailored to patient-specific characteristics.
2025-09-19 | Discovery and validation of small molecule stabilizers of mutant triose phosphate isomerase (TPI) as potential lead candidates for TPI deficiency.
Triosephosphate Isomerase deficiency (TPI-Df) is a devastating untreatable childhood metabolic disease resulting in anemia, severe locomotor impairment, and premature death. Numerous single amino acid substitutions in TPI are pathogenic and result in rapidly progressing multisystem disease. Importantly, all known pathogenic TPI-Df mutations result in a protein that retains function, and pathogenesis is known to result from decreased steady state levels of the functioning protein. There are no small molecule therapies for TPI-Df; current treatments are limited to symptomatic support and dietary interventions. We reasoned that a phenotypic screen was most appropriate to capture agents that stabilize mutant TPI and developed a human cellular TPI-Df assay based on a cellular model of the "common" TPIE105D mutant protein fused with a GFP and a fluorescent ROS biosensor. The assay was implemented for high-content, high-throughput imaging, optimized to full HTS standards, and used to screen a 2,560 compound pilot library and the 220,700 compound NIH MLSMR compound collection to identify candidate compounds for development into small molecule TPI-Df therapies. Hits were validated in dose-response, TPI-Df patient cells, and various orthogonal assays. Limited SAR revealed three promising compound series, which were evaluated for potential mechanisms of action. The lead series had previously been identified as inducers of HIF1 alpha, spawning a novel hypothesis that HIF1 alpha activation might be a potential avenue to treat TPI-Df patients. A lead molecule was moved into preliminary mouse studies to evaluate pharmacokinetics and tissue distribution and was shown to be moderately brain-penetrant. The lead compound is now positioned for target identification studies and efficacy testing in vivo TPI Df models, including a newly validated mouse model.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.