ArticleMolecular therapy : the journal of the American Society of Gene Therapy2008
TAT-mediated delivery of LAD restores pyruvate dehydrogenase complex activity in the mitochondria of patients with LAD deficiency.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 40 citations in OpenAlex.
- Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment.International journal of molecular sciences · 2025Article
- dldhcri3 zebrafish exhibit altered mitochondrial ultrastructure, morphology, and dysfunction partially rescued by probucol or thiamine.JCI insight · 2024Article
- Lipoamide dehydrogenase (LADH) deficiency: medical perspectives of the structural and functional characterization of LADH and its pathogenic variants.Biologia futura · 2023Review
- Review
- Efficient Colon Cancer Immunogene Therapy Through Co-Delivery of IL-22BP mRNA and Tumor Cell Lysate by CLSV Nanoparticles.International journal of nanomedicine · 2023Article
- Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency.JCI insight · 2022Article
- TAT for Enzyme/Protein Delivery to Restore or Destroy Cell Activity in Human Diseases.Life (Basel, Switzerland) · 2021Review
- TAT-Conjugated NDUFS8 Can Be Transduced into Mitochondria in a Membrane-Potential-Independent Manner and Rescue Complex I Deficiency.International journal of molecular sciences · 2021Article
- An Updated View on the Molecular Pathomechanisms of Human Dihydrolipoamide Dehydrogenase Deficiency in Light of Novel Crystallographic Evidence.Neurochemical research · 2019Review
- Import of TAT-Conjugated Propionyl Coenzyme A Carboxylase Using Models of Propionic Acidemia.Molecular and cellular biology · 2018Article
- TAT-MTS-MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM-deficient cells.Journal of cellular and molecular medicine · 2018Article
- Breaking in and busting out: cell-penetrating peptides and the endosomal escape problem.Biomolecular concepts · 2017Review
- Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling.The Journal of clinical investigation · 2017Article
- Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia.Molecular genetics and metabolism reports · 2016Article
- Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency.European journal of pediatrics · 2014Article
- Replacement of the C6ORF66 assembly factor (NDUFAF4) restores complex I activity in patient cells.Molecular medicine (Cambridge, Mass.) · 2013Article
- Transduction of human recombinant proteins into mitochondria as a protein therapeutic approach for mitochondrial disorders.Pharmaceutical research · 2011Review
- The Heart in Friedreich's Ataxia: Basic Findings and Clinical Implications.Progress in pediatric cardiology · 2011Article
- Cardiomyopathy of Friedreich's ataxia: use of mouse models to understand human disease and guide therapeutic development.Pediatric cardiology · 2011Article
- Successful TAT-mediated enzyme replacement therapy in a mouse model of mitochondrial E3 deficiency.Journal of molecular medicine (Berlin, Germany) · 2011Article
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4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Modern medicine offers no cure for mitochondrial disorders such as lipoamide dehydrogenase (LAD) deficiency. LAD is the E3 subunit shared by alpha-ketoacid dehydrogenase complexes in the mitochondrial matrix, and these complexes are crucial for the metabolism of carbohydrates and amino acids. We propose a novel concept for restoring the activity of an immense multicomponent enzymatic complex by replacing one mutated component, the LAD subunit. Our approach entails the fusing of LAD with the transactivator of transcription (TAT) peptide, which is capable of rapidly crossing biological membranes, thereby allowing TAT-LAD to be delivered into cells and their mitochondria where it can replace the mutated endogenous enzyme. Our results show that TAT-LAD is indeed delivered into the cells and their mitochondria, where it is processed, restoring LAD activity to normal values and, most importantly, increasing the activity of pyruvate dehydrogenase complex. We report here, for the first time, that TAT-mediated replacement of one mutated component restores the activity of an essential mitochondrial multicomponent enzymatic complex in cells of patients with enzyme deficiencies. We believe that this approach involving TAT-mediated enzyme replacement therapy (ERT) can be applied to the treatment of LAD deficiency as well as to other mitochondrial and metabolic disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.