Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Kripps, Kimberly A.; Nakayuenyongsuk, Warapan; Shayota, Brian J.; Berquist, William; Gomez‐Ospina, Natalia; Esquivel, Carlos O.; Concepción, Waldo; Sampson, Jacinda B.; Cristin, David J.; Jackson, Whitney E.; Gilliland, Samuel; Pomfret, Elizabeth A.; Kueht, Michael; Pettit, Rowland W.; Sherif, Youmna A.; Emrick, Lisa; Elsea, Sarah H.; Himes, Ryan; Hirano, Michio; Hove, Johan L.K. Van; Scaglia, Fernando; Enns, Gregory M.; Larson, Austin

doi:10.1016/j.ymgme.2020.03.001

Cited by 28 publications

(23 citation statements)

References 13 publications

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“…The following statements are based on 25 class IV level studies (one retrospective cohort, one case series, 24 case reports) 6,7,13,14,37‐58 and expert opinion.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

Hirano

Carelli

Giorgio

et al. 2020

J of Inher Metab Disea

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory

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“…The following statements are based on 25 class IV level studies (one retrospective cohort, one case series, 24 case reports) 6,7,13,14,37‐58 and expert opinion.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

Hirano

Carelli

Giorgio

et al. 2020

J of Inher Metab Disea

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“…Over the last few years, gene therapy has been proposed to reduce the relevant risks associated with the currently available options to treat MNGIE (allogeneic stem cell transplantation and orthotopic liver transplantation) [11][12][13][15][16][17][18]34]. Since the first proof-ofconcept preclinical studies demonstrating the feasibility of using lentiviral [22] and AAV vectors [23], several studies have shown that these strategies provide maintained effectiveness at long term in the preclinical model [19][20][21]24].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is an aggressive therapy associated with a high mortality risk due to transplant-related complications, which are aggravated in MNGIE patients by the poor clinical condition when most are treated [13]. More recently, orthotopic liver transplantation was proposed as an alternative option [14], and the reported cases indicate that successful engraftment results in a sustained nucleoside reduction [15][16][17][18]. However, liver transplantation is also an aggressive intervention, and it is constrained by a limited supply of donors.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides

et al. 2020

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Background: Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches. Methods: dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8-11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals. Findings: Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy. Interpretation: Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype. Funding: This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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“…In the presence of abnormal neurological features in DGUOK deficiency, liver transplantation was not associated with increased survival and therefore should not be considered [ 147 ]. In 6 patients with MNGIE, including one child, OLT was associated with 100% survival, significant improvement in nucleosides levels, and stabilization of clinical course with short term follow up [ [148] , [149] , [150] ] . OLT also led to clinical and biochemical improvement in three patients with ethylmalonic encephalopathy [ 151 , 152 ].…”

Section: Solid Organ and Stem Cell Transplantationmentioning

confidence: 99%

Clinical trials in mitochondrial disorders, an update

Almannai

El‐Hattab

Ali

et al. 2020

Molecular Genetics and Metabolism

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Mitochondrial disorders comprise a molecular and clinically diverse group of diseases that are associated with mitochondrial dysfunction leading to multi-organ disease. With recent advances in molecular technologies, the understanding of the pathomechanisms of a growing list of mitochondrial disorders has been greatly expanded. However, the therapeutic approaches for mitochondrial disorders have lagged behind with treatment options limited mainly to symptom specific therapies and supportive measures. There is an increasing number of clinical trials in mitochondrial disorders aiming for more specific and effective therapies. This review will cover different treatment modalities currently used in mitochondrial disorders, focusing on recent and ongoing clinical trials.

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Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Cited by 28 publications

References 13 publications

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides

Clinical trials in mitochondrial disorders, an update

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