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

Abstract

Orphan technologies for the purpose of attending a rare disease conference in Israel and a license fee payment from Orphan Technologies. She has received research support from the Purine Metabolic Patients Association, Medical Research Council, United Mitochondrial Disease Foundation and the Higher Education Funding Council of England. M.D.B. has received a license fee payment from Orphan Technologies.

Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

“…Diverticula, secondary to the severe gut dysmotility, may lead to complications of gut perforation and require emergency abdominal surgery [75] . Malnutrition is a critical issue for the majority of patients and, although enteral or parenteral nutritional support is often administered, this has not been shown to alter the disease trajectory [76][77][78] . Nasogastric nutrition is poorly tolerated by some patients due to the gastrointestinal dysmotility and long-term total parenteral nutrition use has been reported to be associated with hepatic steatosis and elevated transaminases [16,47,79] .…”

“…Nasogastric nutrition is poorly tolerated by some patients due to the gastrointestinal dysmotility and long-term total parenteral nutrition use has been reported to be associated with hepatic steatosis and elevated transaminases [16,47,79] . The administration of total parenteral nutrition should be carefully considered, as the lipid components are metabolised by the mitochondrion, the site of the primary pathology in MNGIE [77] . Portal hypertension, complicated by ascites and oesophageal varices, may also develop and these are treated as in other conditions [48] .…”

“…The first is the direct removal of the elevated deoxyribonucleosides and includes haemodialysis and continuous ambulatory peritoneal dialysis (CAPD) [11,63,74] . The second strategy is the introduction of the deficient enzyme, thymidine phosphorylase, and includes platelet infusions [26] , allogeneic haematopoietic stem cell transplantation (AHSCT) [46,82,83] , erythrocyte encapsulated thymidine phosphorylase (EE-TP) [77,84] and orthotopic liver transplant (OLT) [85] . These are individually discussed below.…”

“…Regular intravenous administrations of EE-TP aim to provide a sustained reduction or elimination of plasma thymidine and 2'-deoxyuridine concentrations and thereby relieve the nervous system and muscle of the toxic effects of the accumulated metabolites. EE-TP has the pharmacological advantages of prolonging the circulatory half-life of the enzyme and potentially minimising immunogenic reactions, which are frequently observed in enzyme replacement therapies administered by the conventional route [48,77,84,97] .…”

“…In another patient, significant clinical improvements were reported in bilateral muscle power (wrist and first finger abduction, knee flexion, ankle dorsiflexion and great toe extension), gait and balance, sensory ataxia and fine finger function, after 23 months of monthly EE-TP administrations. Body weight increased from 57.4 to 63.2 kg, and a fall in plasma creatine kinase activity from 1200 U/L pre-therapy to levels within the normal reference range was reported [77,84] . Patient reported outcomes included an ability to walk longer distances, climb stairs without assistance, tie shoe laces, feel the sensation of sand and a return to weight training and guitar playing [84] .…”