Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp^-/-Upp1^-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.

Keywords: HSCGT; HSCT; MNGIE; lentiviral vector; metabolic disease; mitochondrial neurogastrointestinal encephalomyopathy; thymidine phosphorylase.

FIGURE 1

Brain MRI findings in MNGIE. MRI of MNGIE patient at age 16 with “typical” MNGIE phenotype. (A) T1 weighted sagital image shows cerebellar vermis atrophy (arrow) and normal gyral pattern. (B) Axial T2 with hyperintensities in the dorsal pons and mesencephalon (arrow). (C coronal flair image, D axial T2) Show extensive signal abnormalities in the cerebral white matter. The external capsule is involved as is the inner blade of the corpus callosum (arrow C,D). (E,F) Extensive white matter involvement with sparing of the U-fibers (arrow).

FIGURE 2

Schematic representation of autologous hematopoietic stem cell based gene therapy for MNGIE and possible mechanism of biochemical correction by gene modified HSCs. (A) Autologous bone marrow (BM) aspirates or apheresis of peripheral blood HSCs (PBSCs) after treatment with rh-G-CSF or plerixafor are collected from MNGIE patient. HSCs are ex vivo transduced by GMP grade lentiviral vectors containing the human TYMP transgene. Before infusion of the transduced cells, MNGIE patients are pre-treated with non-myeloablative conditioning to allow minimal engraftment of gene modified HSCs. Selection and ex vivo expansion of gene modified HSCs allows for transplantation of large numbers of gene modified HSCs to obviate the need for myeloablative pre-conditioning and allows (to some degree) for assessment of safety of the gene modified HSCs prior to transplantation, for example by lentiviral vector integration analysis (reviewed in Watts et al., 2011). (B) The enzyme thymidine phosphorylase (TP) is deficient in all tissues of MNGIE patients, which leads to accumulation of the nucleoside substrates dThd and dUrd and depletion of the nucleotide dCTP and finally mtDNA depletion and deletion (Gonzalez-Vioque et al., 2011). Following transplantation of gene modified HSCs and homing to bone marrow, these cells differentiate into all types of blood cells, LV genome and human TYMP transgene are integrated in leukocyte DNA ensuring stable expression of TP. TP catalyzes the chemical reaction which breaks down the nucleosides. This process eventually leads to reduction of systemic nucleosides accumulation. NTs mediate nucleosides transfer via passive facilitated diffusion (ENTs) and active transport (CNTs), the ubiquitous bidirectional ENTs are depicted (Young et al., 2013). In addition, some gene modified HSCs differentiate into monocytes and may migrate to the brain giving rise to microglia which act as a TP reservoir and cross correct the other cells in CNS.