MICA: Clinical development of erythrocyte encapsulated thymidine phosphorylase - a therapy for mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)) is an almost invariably fatal inherited metabolic disorder caused by a defect in the gene coding for the enzyme thymidine phosphorylase, resulting in affected individuals producing little or no active enzyme. Thymidine phosphorylase is required for the normal metabolism of the metabolites thymidine and deoxyuridine and in its absence these metabolites accumulate in the body causing damage to the mitochondria, the powerhouse of the cell. Energy dependent tissues such as skeletal muscle and nervous system are therefore adversely affected, manifesting clinically as gastrointestinal dysmotility (for example, vomiting and anorexia), neuropathy (nerve damage leading to, for example, loss of sensation and abnormal eye movements) and severe muscle weakness. MNGIE is relentlessly progressive with patients dying at an average reported age of 37.6 years. Matched bone marrow transplants offer a potential cure but are limited by the availability of a matched donor, carry significant risks of serious complications and have a reported mortality as high as 50%. Currently they are not recommended for those patients who have advanced disease. The research team at St. George's, University of London are world leaders in developing the red blood cell (erythrocyte) as a vehicle for carrying (i.e. encapsulating) therapeutic proteins in the blood. In the current study they are investigating the effectiveness of using the patient's own red blood cells to carry the missing thymidine phosphorylase in the circulation. The red blood cells provide a protected environment in which the enzyme can function. The encapsulated enzyme reduces the levels of toxic metabolites in the blood, thus relieving the nervous system and muscle of their damaging effects. Data obtained from the compassionate use of erythrocyte encapsulated thymidine phosphorylase (EE-TP) in two patients with MNGIE shows that a reduction in plasma thymidine and deoxyuridine concentrations can be causally linked to clinical benefit. The aim of this project is to confirm the safety and clinical effectiveness of EE-TP in a European-wide clinical study in ten patients with MNGIE. Successful results from this study will support applications to the regulatory authorities for a marketing license for EE-TP and ensuring patients globally have equitable access.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive metabolic disorder caused by a deficiency in thymidine phosphorylase, which leads to a pathological accumulation of thymidine and deoxyuridine. The disease is relentlessly progressive, and patients die at an average age of 37.6 years. Allogeneic haematopoietic stem cell transplantation (HSCT) offers a potential cure, but carries a high mortality risk. Most patients are ineligible for HSCT due to the current restriction to those without irreversible end-stage disease and with an optimally matched donor. Thus there is a critical requirement to develop an alternative treatment. Our aim is to obtain marketing authorization for our orphan designated enzyme replacement therapy, erythrocyte encapsulated thymidine phosphorylase (EE-TP). In this approach the deficient enzyme is encapsulated within the patient's own erythrocytes in vitro which are then returned to the patient enabling the elimination of the pathological plasma metabolites. A pre- Good Manufacturing Practice (GMP) compliant manufacturing process for thymidine phosphorylase has been established, and Good Laboratory Practice (GLP) pre-clinical studies of EE-TP have revealed no potential serious toxicities that would preclude the clinical use of EE-TP. Clinical compassionate studies of EE-TP in two patients have demonstrated clinical and biochemical benefit. This project will be conducted in three phases: 1) establishing and validating essential processes required for meeting regulatory requirements for operating the clinical phase of this project; 2) conducting a multi-centre (pan European), open-label, multiple ascending dose, Phase II trial in 10 patients with MNGIE, over 36 months; 3) clinical data analysis, dissemination of study results and assembly of regulatory documentation to support the safety, tolerability and efficacy of EE-TP in the treatment of MNGIE for marketing authorization.

Who might benefit from this research?
* Patients, their carers and families.
* Health care professionals: neurologists, gastroenterologists, haematologists, geneticists and community health workers who manage patients with MNGIE. Teams working within the bone marrow transplantation services who have drafted guidelines for the use of HSCT to treat patients with MNGIE.
* Scientists and academics working in the fields of mitochondrial disorders, inherited metabolic diseases, cell therapies and other novel pharmaceutical therapies.
* Biotechnology and pharmaceutical companies aiming to develop enzyme replacement therapies and novel therapies for the treatment of rare diseases.
* Groups responsible for enacting or influencing legislation on the treatment of rare conditions, for example, Rare Disease UK Working Groups, National Specialised Commissioning Group, The National Institute for Clinical Excellence, Department of Health, European Commission Rare Diseases Task Force (RDTF), Committee for Orphan Medicinal Products (COMP) at the EMEA, and Engagement of European Organisation for Rare Diseases (EURORDIS).
* Resource Centres for example, Orphanet (www.orpha.net), OrphaNews Europe, the European Platform for Patients' Organisations, Science and Industry (Epposi). Charities which support patients with rare inherited metabolic diseases, for example, PUMPA, Climb, United Mitochondrial Disease Foundation, and the Muscular Dystrophy Campaign.

How might they benefit from this research?
The research will improve the awareness of this rare disorder due to the availability of a specific therapy. This will encourage earlier diagnosis and thus the likely success of all therapies for this condition. Patients will gain access to a therapy which enhances the quality of life and provides significant health benefits. Health care systems will realize reductions in treatment costs due to reduced hospital admissions and avoidance of alternative care costs such as parenteral nutrition and palliative care. The rare disease community consisting of patients, their carers and families, health care professionals, scientists, charities, and resource centres will benefit from knowledge generated from this research, encouraging dialogue and the formation of partnerships and networks. In the case of MNGIE this could lead to an international clinical network to advance therapies and establish a disease registry that is currently lacking. Outside MNGIE, the identification of biomarkers of mitochondrial disruption and their correlation with clinical status that would be part of the clinical trial would extend scientific and therapeutic benefits to other mitochondrial diseases. The application of red cell-based therapies as a primary therapy rather than an alternative to a pre-existing therapy could stimulate European research activities in the field of drug delivery and rare diseases, enabling the development of new protocols and novel drug delivery systems. Research findings may provide information to public policy groups and initiatives for advancing national and international healthcare policy formation. The transfer of innovative expertise to collaboration partners will promote and accelerate the growth of innovative industrial activity, contribute to the increasing competitiveness of Europe in the field of cell-based therapy delivery and reduce the time-to-market.