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

Lead Research Organisation: St George's University of London
Department Name: Molecular & Clinical Sci Research Inst

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description External Expert Advisor to the Department of Health, Gene Therapy Advisory Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Provided coments on gene therapy proposal for a clinical trial
 
Description Membership of St George's Ethic's committee
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
Impact Reviewing the ethical aspects of projects including: • methods of collection of existing data, documents or records which are publicly available (non-NHS sources) • the use of existing data, documents or records to ensure participants cannot be identified • the use of educational tests, surveys, interview procedures or observations of public behaviour to ensure participants cannot be identified and there are no risk of adverse treatment through participation •there are no controversial ethical aspects .
 
Description Equipment Fund
Amount £8,650 (GBP)
Organisation Purine Metabolic Patients’ Association (PUMPA) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2016 
End 07/2016
 
Description Equipment Grant
Amount £17,000 (GBP)
Organisation Neopharm 
Sector Private
Country Israel
Start 05/2015 
 
Description Molecular and Clinical Sciences Research Institute Funding
Amount £6,371 (GBP)
Organisation St George's University 
Sector Academic/University
Country Grenada
Start 03/2017 
End 07/2017
 
Description Molecular and Clinical Sciences Research Institute Funding
Amount £6,274 (GBP)
Organisation St George's University 
Sector Academic/University
Country Grenada
Start 05/2017 
End 11/2017
 
Description Molecular and Clinical Sciences Research Institute Funding (IPA software)
Amount £9,542 (GBP)
Organisation St George's University 
Sector Academic/University
Country Grenada
Start 12/2017 
End 11/2018
 
Description Pilot study Extended expression profiling study of Cerebral Organoids
Amount £4,787 (GBP)
Organisation Purine Metabolic Patients’ Association (PUMPA) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 09/2017
 
Description Pilot study Extended miRNA expression profiling study
Amount £10,000 (GBP)
Organisation Purine Metabolic Patients’ Association (PUMPA) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 12/2017
 
Description Postdoctoral salary fund
Amount £22,754 (GBP)
Organisation Orphan Technologies 
Sector Private
Country Switzerland
Start 04/2018 
End 09/2018
 
Description Research Funding
Amount £37,000 (GBP)
Funding ID LILY-2017.18 (APPLICATION 3 - BAX) 
Organisation The Lily Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2020
 
Description Specialised Patient Care
Amount £999,420 (GBP)
Funding ID WEF010812 
Organisation Mid Hampshire Primary Care Trust 
Start 08/2012 
End 07/2017
 
Description Specialised patient Care (value below is per year and termination date is unknown)
Amount £38,412 (GBP)
Organisation Italian Health Service 
Sector Public
Country Italy
Start 12/2013 
 
Description The development of knock-out cell culture models for investigating the underlying molecular mechanisms that contribute to the neuronal aspects of Mitochondrial Neurogastrointestinal Encephalomyopathy
Amount £142,133 (GBP)
Organisation Purine Metabolic Patients’ Association (PUMPA) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 03/2018
 
Title GLP immunoassay for EE-TP clinical trial 
Description Validated immunoassay for the measurement of human anti-thymidine phosphorylase antibodies in patients treated with EE-TP 
Type Of Material Biological samples 
Year Produced 2017 
Provided To Others? No  
Impact Supporting documentation for clinical trial of EE-TP 
 
Title GMP -TP 
Description Production of three batches of GMP thymidine phosphorylase for a clinical trial of EE-TP for the treatment of MNGIE 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Three validation batches have provided data to support IMPD and pre-submission briefing package to EMA 
 
Title Validated HPLC assay 
Description Assay validated for the measurement of EE-TP to support QP release in Clinical trial 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Quantification of doses given to patients in compassionate use 
 
Title Validated immunoassay 
Description Immunoassay for detection of human antibodies against thymidine phosphorylase 
Type Of Material Biological samples 
Year Produced 2016 
Provided To Others? No  
Impact Support Clinical trial 
 
Title iPSC of MNGIE and healthy controls 
Description We have developed iPSCs of MNGIE and healthy controls to further the understanding of the molecular mechanisms that underlie MNGIE. Cerebral organoids have been created 
Type Of Material Cell line 
Year Produced 2017 
Provided To Others? Yes  
Impact Data obtained will support the submission of a PhD thesis. Model to replace mouse double knock-out 
URL http://www.nmd-journal.com/article/S0960-8966(17)30270-5/fulltext
 
Title miRNA target database in MNGIE 
Description MiRNA profile database of serum samples from MNGIE patients 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Collaboration in bioinformatics 
 
Description Automation of drug encapsulation 
Organisation Cell and Gene Therapy Catapult
Country United Kingdom 
Sector Private 
PI Contribution Currently in discussions with regard to the design and production of an automated process
Collaborator Contribution Currently in discussions with regard to the design and production of an automated process
Impact Knowledge exchange
Start Year 2014
 
Description Bioinformatics collaboration 
Organisation University of Lisbon
Country Portugal 
Sector Academic/University 
PI Contribution Sharing data for bioinformatic analysis
Collaborator Contribution Training in the use of bioinformatic databases, and pathway analysis
Impact miRNA- gene target networks Enrichment analysis of miRNA targets PhD thesis
Start Year 2015
 
Description Characterisation of biomarkers for monitoring disease progression and treatment efficacy in MNGIE 
Organisation St George's University of London
Department Department of Basic Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysed preliminary data and wrote/submitted grant application,
Collaborator Contribution Provided guidance on the appropriate techniques to be employed in project
Impact Funding for a PhD studentship
Start Year 2011
 
Description Commercial partnership 
Organisation Orphan Technologies
Country Switzerland 
Sector Private 
PI Contribution Intellectual knowledge, expertise in EE-TP manufacture, knowledge of disease (MNGIE)
Collaborator Contribution Expertise in regulatory issues, manufacturing to GMP, clinical trial activities
Impact Recent submission of DPFS/DCS MRC application
Start Year 2012
 
Description FLT 
Organisation Newcastle University
Department Northern Institute for Cancer Research Newcastle
Country United Kingdom 
Sector Academic/University 
PI Contribution Assay of thymidine and thymidine phosphorylase Knowledge sharing Supply of Thymidine phosphorylase
Collaborator Contribution In progress: Administration of E. coli thymidine phosphorylase (TP) to human tumour xenograft models in mice with the aim of depleting tumour thymidine levels and improve tumour imaging with 18F-FLT PET/CT
Impact MRC Confidence in Concept (CiC) Funding award- 14,891.01
Start Year 2014
 
Description MNGIE: An Italian network for MNGIE epidemiology, molecular mechanisms and enzyme replacement therapy by stem cell transplant 
Organisation University Hospital Spedali Civili
Department Clinical Neurology
Country Italy 
Sector Academic/University 
PI Contribution Sharing data obtained from the treatment of patients with enzyme replacement therapy with thymidine phosphorylase
Collaborator Contribution The research team has diagnosed two patients with MNGIE via this collaboration, providing the research team with two potential patients for the Clinical trial they are intending to initiate. Plasma and urine samples have been donated to the research team's Biomarker study.Supply of plasma and urine samples for Research team's Biomarker study
Impact A network of Italian clinicians (neurologists, gastroenterologists) and European researchers has been established, who have experience in MNGIE. The aim is to share information in order to better understand the frequency, natural history and clinical aspects of this complex and rare disease, and to share protocols for both pre-treatment and follow-up studies.
Start Year 2011
 
Description MNGIE: An Italian network for MNGIE epidemiology, molecular mechanisms and enzyme replacement therapy by stem cell transplant 
Organisation University of Verona
Department Department of Neurological Sciences and Vision
Country Italy 
Sector Academic/University 
PI Contribution Sharing data obtained from the treatment of patients with enzyme replacement therapy with thymidine phosphorylase
Collaborator Contribution The research team has diagnosed two patients with MNGIE via this collaboration, providing the research team with two potential patients for the Clinical trial they are intending to initiate. Plasma and urine samples have been donated to the research team's Biomarker study.Supply of plasma and urine samples for Research team's Biomarker study
Impact A network of Italian clinicians (neurologists, gastroenterologists) and European researchers has been established, who have experience in MNGIE. The aim is to share information in order to better understand the frequency, natural history and clinical aspects of this complex and rare disease, and to share protocols for both pre-treatment and follow-up studies.
Start Year 2011
 
Description MiRNA profiling in MNGIE 
Organisation Integrated University Hospital Verona
PI Contribution miRNA profiling and bioinformatic analysis of of plasma samples
Collaborator Contribution Patient samples
Impact Poster presentation at the Annual Neuromuscular Translational Research Conference 2017. Oral presentation at the 17th Symposium of the Purine and Pyrimidine Society conference and prize awarded for best presentation. Successful funding from the Lily Foundation to continue study.
Start Year 2017
 
Description Principal Investigators for trial of EE-TP 
Organisation Azienda Ospedaliera Spedali Civili di Brescia
Country Italy 
Sector Hospitals 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Description Principal Investigators for trial of EE-TP 
Organisation St George's Hospital
Department Department of Neurology
Country United Kingdom 
Sector Hospitals 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Description Principal Investigators for trial of EE-TP 
Organisation University College London
Department Department of Applied Health Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Description Principal Investigators for trial of EE-TP 
Organisation University Hospital of Montpellier
Country France 
Sector Hospitals 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Description Principal Investigators for trial of EE-TP 
Organisation University of Bonn
Department Department of Neurology
Country Germany 
Sector Hospitals 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Description Principal Investigators for trial of EE-TP 
Organisation University of Verona
Country Italy 
Sector Academic/University 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Description Principal Investigators for trial of EE-TP 
Organisation Western Galilee Medical Centre in Nahariya
Country Israel 
Sector Hospitals 
PI Contribution Academic discussions with regard to the patient population under study and input into the trial design and regulatory briefing package.
Collaborator Contribution Clinical and academic staff of the above institutions were identified as principal Investigators for clinical trial sites for the pending clinical trial of EE-TP. Contributions have included intellectual knowledge with regard to the patient population under study and input into the trial design and regulatory briefing package
Impact Pre-submission briefing package for scientific advice from EMA Clinical trial synopsis and protocol Poster presentation to Annual Neuromuscular Translational Research Conference 2017
Start Year 2016
 
Title EE-TP therapy for MNGIE disease 
Description Enzyme replacement therapy for a rare inherited metabolic disease. Enzyme is encapsulated in patients red blood cells. 
IP Reference GB1116767.3 
Protection Patent application published
Year Protection Granted 2012
Licensed Yes
Impact Increased awareness in patient and clinician community. Requests for compassionate use. International Health authorities funding compassionate therapy.
 
Title Treatment for mitrochondrial neurogastrointestinal Encephalomyopathy (MNGIE) 
Description New European Patent Application No. 12756551.3 National Phase of PCT/GB2012/052157 
IP Reference 12756551.3 
Protection Patent application published
Year Protection Granted 2014
Licensed Yes
Impact Clinical trial funding
 
Title Erythrocyte encapsulated thymidine phosphorylase using an automated manufacturing process 
Description Erythrocyte encapsulated thymidine phosphorylase manufactured using an automated GMP manufacturing process has been employed in the compassionate use setting. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Other impacts include supporting data for our clinical trial protocol and regulatory package development 
 
Title Erythrocyte encapsulated thymidine phosphorylase 
Description A red cell loading device has been validated for the encapsulation of thymidine phosphorylase into erythrocytes. Its use has been applied in the compassionate treatment setting prior to moving into a clinical trial which is due to start mid 2018. 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Validation data has supported the development of our study protocol, and regulatory package 
 
Title GMP Working Cell bank for thymidine phosphorylase 
Description The product under development is erythrocyte encapsulated thymidine phosphorylase (EE-TP) for the treatment of MNGIE. The thymidine phosphorylase developed is a recombinant enzyme and to date thre engineering batches have been produced for clinical trial use. Master and working cell banks have been created. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact The product has been employed in the compassionate use setting and has eliminated previously observed immune reactions that were observed using a less purified version 
 
Title GMP thymidine phosphorylase 
Description The manufacture of two GMP batches of thymidine phosphorylase for clinical trial use (Q3 2018) 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact This material will be used in our clinical trial of erythrocyte encapsulated thymidine phosphorylase which is due to start in mid 2018 
 
Title GMP thymidine phosphorylase 
Description The product under development is erythrocyte encapsulated thymidine phosphorylase (EE-TP) for the treatment of MNGIE. The thymidine phosphorylase developed is a recombinant enzyme and to date three engineering batches have been produced for clinical trial use. Master and working cell banks have been created. The development is funded by the MRC. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact Documentation from manufacture will support clinical trial application 
 
Title GMP thymidine phosphorylase 
Description Three validation batches of GMP enzyme. Associated documentation will be used to support clinical trial application. Material will be employed in clinical trial starting 2016. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact Impact- support clinical trial 
 
Title Master cell bank 
Description Master Cell Bank for production of GMP thymidine phosphorylase 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact Employed to produce three validation batches of GMP enzyme for clinical trial use and for regulatory approval 
 
Description How to achieve funding support from the MRC 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Provided a presentation on the experiences of a MRC grant holder
Year(s) Of Engagement Activity 2017
 
Description Rare Disease Day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International MNGIE Consortium Meeting and Innsbruck Rare Disease Day Symposium 2016

Monday, February 29 2016, Innsbruck
Presentation of recent / interesting issues:
Discussions on Liver cirrhosis in MNGIE, liver transplantation and gene therapy using an AAV vector
Year(s) Of Engagement Activity 2016