{"id":"03786","slug":"anaplerotic-tca-cycle-prodrugs--03786","source":{"id":"03786","dataset":"techtransfer","title":"Anaplerotic TCA Cycle Prodrugs for Restoring Mitochondrial Metabolism for Organic Acidemia and Fatty Acid Oxidation Disorders","description_":"<p>These prodrugs comprise a glycerol backbone esterified at one or more positions with tricarboxylic acid (TCA) cycle moieties—such as succinate, malate, fumarate, citrate, isocitrate, cis-aconitate or α-ketoglutarate—via short alkyl linkers. Exemplified by trisuccinylglycerol (TSG), these agents enter PCC- or MUT-deficient cells and release multiple anaplerotic substrates to replenish depleted TCA intermediates. In vitro studies using ¹⁴C-palmitate demonstrate restored mitochondrial flux, while in vivo experiments in mouse models of propionic and methylmalonic acidemia show improved survival and normalized metabolite profiles. Human subjects receiving oral or intravenous dosing once or several times daily exhibit normalized blood and urine analytes and improved cardiac function, highlighting effective delivery and systemic correction of metabolic imbalance.</p><p><h2>Description</h2>This approach is differentiated by its multi-moiety design that delivers a spectrum of TCA substrates in a single molecule, rather than relying on single-substrate supplementation. The glycerol ester scaffold permits fine-tuning of lipophilicity and hydrolysis rates through R¹ (H or C₁–C₆ alkyl) linkers, optimizing cell permeability and controlled release. By bypassing specific enzymatic blockades in propionyl-CoA carboxylase and methylmalonyl-CoA mutase deficiencies, these prodrugs restore whole-cycle function more comprehensively than conventional dietary or simple anaplerotic treatments. Their oral and intravenous flexibility, coupled with robust preclinical and clinical data, underscores a novel therapeutic paradigm for inborn errors of metabolism.</p><p><h2>Applications</h2>- Propionic acidemia oral therapy\r<br>- Methylmalonic acidemia IV therapy\r<br>- Fatty acid oxidation disorder treatment\r<br>- Mitochondrial TCA cycle replenishment\r<br>- Treatment for cardiomyopathy and other heart complications associated with organic acidemias.\r<br>- Therapy for other genetic defects in the propionate metabolic pathway, such as Succinyl-CoA lyase deficiency.</p><p><h2>Advantages</h2>- Replenishes TCA cycle intermediates and restores mitochondrial flux \r<br>- Improves metabolic profiles and survival rates in PA/MMA animal models\r<br>- Normalizes blood and urine analytes in human subjects with PA and MMA\r<br>- Enhances cardiac function in patients with cardiomyopathy\r<br>- Enables flexible oral or intravenous dosing regimens\r<br>- The pro-drug formulation (Trisuccinylglycerol) is designed to improve the pharmacological delivery and bioavailability of succinate compared to the unformulated compound</p><p><h2>Invention Readiness</h2>The technology's efficacy has been demonstrated in relevant in vitro models, specifically using patient cell lines deficient in Propionyl-CoA Carboxylase (PCC). Initial experiments have confirmed the compound's ability to correct TCA cycle balance in these cells, with the effect measured by advanced metabolomics of intracellular TCA cycle intermediates. Further studies are planned to advance the technology, beginning with a dosing escalation study in metabolically stable patients to confirm the compound's effect in a human subject. This will be followed by longer-term open-label trials, including a planned three-month study to specifically assess cardiac function. The full clinical development pathway is set to culminate in a double-blind, placebo, cross-over study to demonstrate definitive efficacy.</p><p><h2>IP Status</h2><a target=\"_blank\" href=\"https://patents.google.com/patent/US11083702B2\">https://patents.google.com/patent/US11083702B2</a></p><p></p>","tags":["Genetics","Pediatric Medicine"],"file_number":"03786","collections":[{"key":517,"name":"Cardiometabolic"}],"meta_description":"Multi-substrate glycerol prodrugs replenish TCA intermediates, restoring mitochondrial function in PA/MMA and fatty acid oxidation disorders.","image_url":"","apriori_judge_output":"{\"scores\":{\"novelty\":4.0,\"potential_impact\":4.0,\"readiness\":3.0,\"scalability\":3.0,\"timeliness\":2.0},\"weighted_score\":3.45,\"risks\":[\"Older (2015)—technology aging in evaluation cycle\",\"Limited human data beyond early studies; regulatory path likely complex\",\"Competition in metabolic prodrug space; translational challenges\"],\"one_sentence_take\":\"High novelty and potential impact with a versatile multi-substrate prodrug, but readiness and timeliness are limited given its age and translational hurdles.\"}","lead_inventor_name":"Gerard Vockley","lead_inventor_dept":"Med-Pediatrics","technology_type":"Therapeutic Modality","technology_subtype":"Small Molecule","therapeutic_areas":["Endocrinology and Metabolic Diseases"],"therapeutic_indications":["Other"],"custom_tags":[],"all_tech_innovators":["Al-Walid A. Mohsen","Gerard Vockley"],"date_submitted":"2015-12-14","technology_readiness_level":"5. Drug candidate created"},"highlight":{},"matched_queries":null,"score":0.0}