Pyruvate Dehydrogenase Deficiency (PDD)
Pyruvate dehydrogenase deficiency (PDD) impairs cerebral energy metabolism by blocking pyruvate entry into the TCA cycle, leading to lactic acidosis, neuronal ATP deficit, and progressive neurodegeneration. At Protheragen, we focus on developing novel therapeutics and building accurate animal models to accelerate preclinical studies of potential therapies for PDD. As your trusted partner in PDD drug development research, we provide unparalleled support to meet your research needs.
Introduction to Pyruvate Dehydrogenase Deficiency (PDD)
Pyruvate dehydrogenase deficiency (PDD) is a rare neurometabolic disorder caused by dysfunction of the mitochondrial pyruvate dehydrogenase complex (PDC), a critical enzyme system that bridges glycolysis and the tricarboxylic acid (TCA) cycle. PDC catalyzes the irreversible conversion of pyruvate into acetyl-CoA, a key substrate for oxidative phosphorylation and energy production.
Fig.1 Carbohydrate metabolism. (Karissa P, et al., 2022)
Pathogenesis of Pyruvate Dehydrogenase Deficiency (PDD)
Pyruvate dehydrogenase deficiency (PDD) is fundamentally caused by genetic defects in the pyruvate dehydrogenase complex (PDC), a critical mitochondrial enzyme system that converts pyruvate into acetyl-CoA for energy production. The most prevalent cause involves mutations in the PDHA1 gene (X-linked), which encodes the E1α subunit of PDC, though rarer variants may affect other components (PDHB, DLAT, PDHX). These mutations disrupt PDC function, leading to impaired glucose oxidation, accumulation of pyruvate and lactate, and subsequent energy deficiency in high-demand tissues like the brain and muscles.
Therapeutic Development for Pyruvate Dehydrogenase Deficiency (PDD)
| Drug Names | Mechanism of Action | Targets | Research Phase |
| Thiamine (Vitamin B1) | Acts as a cofactor (thiamine pyrophosphate, TPP) for the E1 subunit of PDC, enhancing residual enzyme activity in thiamine-responsive mutations. | PDHA1 | Approved |
| Carnitine | Facilitates fatty acid oxidation, providing alternative energy sources (ketones) to bypass PDC dysfunction. May reduce toxic acyl-CoA accumulation. | Carnitine palmitoyltransferase (CPT) system | Approved |
| Lipoic Acid | Serves as a cofactor for the E2 (dihydrolipoamide acetyltransferase) subunit of PDC. May mitigate oxidative stress by scavenging ROS. | Dihydrolipoamide S-acetyltransferase | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
As a professional preclinical research service provider, Protheragen is dedicated to accelerating breakthroughs in the field of pyruvate dehydrogenase deficiency (PDD). We offer end-to-end solutions encompassing diagnostic development, novel therapeutic development, precise disease modeling, and rigorous preclinical validation. Our blood-brain barrier model enables critical assessments of drug permeability in the central nervous system (CNS), ensuring optimal brain exposure while minimizing systemic toxicity, thus expediting the development of effective therapies.
Therapeutic Development Services
By Mechanism of Action
Disease Model Development Services
In Vitro Model Development
- PDHA1 Knockout Model: Global, germline deletion of PDHA1 causing systemic pyruvate dehydrogenase deficiency and early postnatal lethality.
- PDHA1 Knockdown Model: Tissue-specific or inducible partial silencing of PDHA1 yielding a hypomorphic state that mimics variable PDH deficiency severity and survival.
At Protheragen, we are committed to validating and optimizing therapies for pyruvate dehydrogenase deficiency (PDD) through preclinical studies including pharmacodynamics (PD), pharmacokinetics (PK) and toxicology to ensure their successful regulatory approval. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
Reference
- Karissa P, Simpson T, Dawson S P, et al. Comparison between dichloroacetate and phenylbutyrate treatment for pyruvate dehydrogenase deficiency[J]. British Journal of Biomedical Science, 2022, 79: 10382.