Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach

Abstract

Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.

Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE

“…Patients undergoing a successful allogeneic HSCT show permanent restoration of TP activity with correction of biochemical abnormalities and progressive improvements in clinical parameters. 4,12,15,16 However, allogeneic HSCT is not an ideal therapy because of toxicity of the conditioning regimen and the risk of severe complications, such as graft failure and graft-versus-host disease. 19 We hypothesized that HSCGT using autologous cells could overcome some of these limitations, and represents a reasonable therapeutic alternative for MNGIE patients.…”

“…2,3 MNGIE is a rare disease, with fewer than 200 patients known to be affected worldwide, but the true incidence of the disease is unknown and calculations based on known cases may lead to underestimations because MNGIE patients are often misdiagnosed. 4 TP catalyzes the phosphorolysis of thymidine (dThd) or deoxyuridine (dUrd) nucleosides to the corresponding bases, thymine or uracil, and deoxyribose-1-phosphate. 5 In MNGIE patients, mutations in TYMP markedly reduce TP activity, resulting in a systemic accumulation of dThd and dUrd.…”

“…7,[11][12][13][14] In recent years, several MNGIE patients have been treated with allogeneic hematopoietic stem cell transplantation (HSCT). 4,12,15,16 After successful HSCT, donorderived nucleated blood cells and platelets provided enough TP activity to reduce the dThd and dUrd concentrations to undetectable or nearly undetectable levels, and subsequent slowing of disease progression or mild clinical improvement. 4,12,15,16 However, this approach has several limitations, which include the high morbidity and mortality of allogeneic HSCT, and the difficulty of obtaining suitable donors for a high proportion of patients.…”

“…In addition, drugs with possible mitochondrial toxicity must be avoided. 4 As occurs with many monogenic disorders that can benefit from an allogeneic HSCT, MNGIE is probably a very good candidate for hematopoietic stem cell gene therapy (HSCGT). Robust and stable TP expression in hematopoietic cells should clear the systemic accumulation of dThd and dUrd, as observed in MNGIE patients undergoing an allogeneic HSCT.…”

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…More than 10 individuals with MNGIE disease have so far been treated with allogeneic HSCT [133][134][135][136]. Allogeneic HSCT has been shown to restore TP activity, lowering thymidine levels and improving the gastrointestinal dysmotility [132][133][134][135].…”