Gene Therapy for MNGIE

Research type

Laboratorium onderzoek

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MNGIE is an inherited mitochondrial disease, characterized by devastating neurological and intestinal symptoms. There is no curative therapy for these patients. We have developed therapeutic lentiviral vectors to genetically engineer autologous stem cells, to restore production of a defective enzyme (thymidine phosphorylase (TP)). This normalizes the biochemical imbalances in MNGIE mice. We expect that this strategy will provide a curative approach to treat MNGIE patients, and will form the basis to treat other mitochondrial and neuromuscular disorders.

Description research

Normally, human cells produce an enzyme called thymidine phosphorylase (TP), which maintains the balance of certain chemicals within the cell. Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) is a fatal disease caused by alterations that stop the TP gene from producing functional TP enzyme. This leads to accumulation of the chemicals to toxic levels. The toxic metabolites interfere with the normal function of the mitochondria (powerhouses of the cells), which eventually leads to life-threatening symptoms. In particular, MNGIE disease damages the intestinal tract. Patients usually show inability to digest or absorb food and are therefore extremely thin and exhausted. Brain abnormality, deafness or loss of vision are common symptoms. It has been attempted to treat MNGIE by bone marrow transplantation (BMT), receiving cells from healthy relatives. However, it is difficult to find a matched donor and the transplantation procedure can be harmful due to application of chemotherapy (necessary for the transplanted cells to engraft).
Our gene therapy approach offers a one-time treatment option. Since patient-derived cells are used, BMT-related morbidity and mortality can be circumvented. A vector is used to deliver a functional copy of the TP gene back into the patient’s bone marrow cells. These corrected cells are infused back into the patient and the new gene produces a functioning TP and therefore reverses or prevents the symptoms. Recently, gene therapy was applied to treat patients of another genetic disease, Wiskott-Aldrich syndrome, with promising resuls (Hacein-Bey Abina S et al. JAMA, 2015). We are curretly testing the efficacy and safety of our therapy in te lab and are preping for the next step to study in MNGIE patients.