scholarly journals Thymidine phosphorylase is both a therapeutic and a suicide gene in a murine model of mitochondrial neurogastrointestinal encephalomyopathy

Gene Therapy ◽  
2014 ◽  
Vol 21 (7) ◽  
pp. 673-681 ◽  
Author(s):  
S López-Estévez ◽  
G Ferrer ◽  
J Torres-Torronteras ◽  
M J Mansilla ◽  
S Casacuberta-Serra ◽  
...  
Keyword(s):  
Murine Model ◽  
Thymidine Phosphorylase ◽  
Suicide Gene ◽  
Mitochondrial Neurogastrointestinal Encephalomyopathy

scholarly journals Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy

2019 ◽  
Vol 8 (4) ◽  
pp. 457 ◽  
Author(s):  
Michelle Levene ◽  
Murray Bain ◽  
Nicholas Moran ◽  
Niranjanan Nirmalananthan ◽  
Joanna Poulton ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Thymidine Phosphorylase ◽  
Dose Range ◽  
Autosomal Recessive Disorder ◽  
Plasma Metabolites ◽  
Serious Adverse Events ◽  
Clinical Safety ◽  
Mitochondrial Neurogastrointestinal Encephalomyopathy ◽  
Enzyme Replacement

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.

scholarly journals AAV6 Vexosomes Mediate Robust Suicide Gene Delivery in a Murine Model of Hepatocellular Carcinoma

2020 ◽  
Vol 17 ◽  
pp. 497-504 ◽  
Author(s):  
Nusrat Khan ◽  
Shubham Maurya ◽  
Sridhar Bammidi ◽  
Giridhara R. Jayandharan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gene Delivery ◽  
Murine Model ◽  
Suicide Gene

scholarly journals MicroRNA‐based recombinant AAV vector assembly improves efficiency of suicide gene transfer in a murine model of lymphoma

2020 ◽  
Vol 9 (9) ◽  
pp. 3188-3201 ◽  
Author(s):  
Nusrat Khan ◽  
Sabna Cheemadan ◽  
Himanshi Saxena ◽  
Sridhar Bammidi ◽  
Giridhara R. Jayandharan
Keyword(s):  
Gene Transfer ◽  
Murine Model ◽  
Suicide Gene ◽  
Aav Vector

scholarly journals Erythrocyte Encapsulated Thymidine Phosphorylase for the Treatment of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy: Study Protocol for a Multi-Centre, Multiple Dose, Open Label Trial

2019 ◽  
Vol 8 (8) ◽  
pp. 1096 ◽  
Author(s):  
Bax ◽  
Levene ◽  
Bain ◽  
Fairbanks ◽  
Filosto ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Thymidine Phosphorylase ◽  
Autosomal Recessive Disorder ◽  
Open Label ◽  
Post Dose ◽  
Mitochondrial Neurogastrointestinal Encephalomyopathy ◽  
Clinical Assessments ◽  
Enzyme Replacement ◽  
Normal Metabolism ◽  
Open Label Trial

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.

scholarly journals Liver as a Source for Thymidine Phosphorylase Replacement in Mitochondrial Neurogastrointestinal Encephalomyopathy

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96692 ◽  
Author(s):  
Elisa Boschetti ◽  
Roberto D’Alessandro ◽  
Francesca Bianco ◽  
Valerio Carelli ◽  
Giovanna Cenacchi ◽  
...  
Keyword(s):  
Thymidine Phosphorylase ◽  
Mitochondrial Neurogastrointestinal Encephalomyopathy
Sign in / Sign up

Export Citation Format

Share Document