Rare Disease and Orphan Drugs Journal (RDODJ) was glad to have a special interview with Dr. Bridget Bax, one of the Editorial Board Members of RDODJ, in terms of her article "Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network". It is the first consensus statement on MNGIE, prompted by the severity of a condition that, although very rare, affects mainly young adults causing substantial reduction of life expectancy and QoL.
Dr. Bridget Bax is a Reader in rare diseases at St George’s, University of London, UK. She focuses on examining the underlying molecular mechanisms of rare diseases and the development of cell-based therapies for diseases with unmet needs. Her research focus is the ultra-rare disease, MNGIE, for which she and her team developed an orphan drug designated cell-based enzyme replacement therapy. The therapy was initially applied to the compassionate treatment of patients with MNGIE before being licensed to Neovii. In 2019 her team obtained UK regulatory approval for a phase 2 clinical trial. Dr.Bax graduated with a B.Sc. (Hons) in Biochemistry from Royal Holloway College, University of London and completed a PhD in Medicine at the Royal Postgraduate Medical School, University of London.
The details of the interview are as follows:
RDODJ: We know you have been working on MNGIE for a long time. What motivates you to keep working in this field? Could you please share something about your team's recent research progresses?
Dr. Bax: MNGIE is a fatal inherited metabolic disorder caused by pathological mutations in the TYMP gene impacting the normal replication of mitochondrial DNA, leading to mitochondrial dysfunction. As with many rare diseases, patients with MNGIE have unmet need; patients experience misdiagnoses and diagnosis delays of up to 10 years, and currently no licensed treatments are available. Our team is working on the development of an enzyme replacement therapy (erythrocyte encapsulated thymidine phosphorylase) for the treatment of MNGIE. The therapy involves encapsulating the deficient enzyme into the patient’s erythrocytes. Patient centricity is a very important aspect of rare disease clinical research, particularly for understanding what symptoms are important to the patient and assessing the potential burden of participation in a study. It has been an amazing privilege for us to have the opportunity to work closely with patients and their families to establish these aspects and to have a clearer understanding of the patient’s journey. The enzyme-replacement project is now licensed to a commercial company for regulatory clinical development. The knowledge that our research has the potential to address one of these unmet needs is what really motivates me.
RDODJ: The article "Mitochondrial neurogastrointestinalencephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network", published in 2021, has attracted many experts' attention. Were there any challenges during the research?
Dr. Bax: This article represents the output from the International Consensus Conference on MNGIE that was held in Bologna, Italy, in March 2019. The aim was to produce the first unbiased, evidence-based assessment on MNGIE, leading to a consensus on the diagnosis, prognosis and treatment of patients with MNGIE. The challenges that faced this piece of work are mainly those associated with the disease being ultra-rare, including limited reported case studies, insufficient natural history data, duplicate reporting, non-standardized data collection, limited patient follow-up and few investigators and centers with disease expertise.
RDODJ: You mentioned in the article that "Our process had several limitations" and elaborated on some limitations in the report. Do you have any suggestions to reduce the regulations?
Dr. Bax: The limitations of the process were mainly due to the small number of reported case studies, insufficient natural history data and the limited number of knowledgeable researchers and clinicians. Since MNGIE is an ultra-rare disease affecting a relatively small number of patients, the most obvious way to reduce these limitations would be through the development of an international collaborative research network that would promote the sharing of standardized diagnosis and treatment protocols, patient natural history and multi-omics data, and biobank material. This was one of the recommendations of the MNGIE Consensus paper.
RDODJ: Could you please talk about the current research hotspots and the prospects in the field of MNGIE?
Dr. Bax: Rare disease biomarker discovery is becoming an active research field and increasingly rare disease drug developers are undertaking biomarker strategies for the purpose of stratifying patients according to disease subtype and expediting drug development programs. We recently conducted an international collaborative study between ten countries involving 20 collaborators where we investigated the utility of microRNAs (miRNAs) as potential circulating biomarkers of MNGIE. MiR-34a-5p was shown to be the single best predictor of disease. A decreased expression of this miRNA was noted in four patients treated with erythrocyte-encapsulated thymidine phosphorylase, thus demonstrating the potential utility of this miRNA in monitoring response to treatment. We believe that this biomarker could be of prognostic value in assessing clinical status and recommend its inclusion in future clinical trials of investigational therapies for MNGIE.
Additionally, a five-year natural history study of twenty patients with MNGIE is currently being conducted by Professor Michio Hirano at Columbia University and this will undoubtedly provide much-needed information on disease status measures that could be employed in future clinical trials.
RDODJ: As an Editorial Board member of the RDODJ, could you please provide some suggestions about which research aspects the journal should primarily focus on in the future to promote the long-term development of RDODJ?
Dr. Bax: Considering the diversity and complexity of rare diseases, I would find it very difficult to suggest a particular research focus for the journal. Importantly, the aims and scope of RDODJ embrace a broad spectrum of research topics that are pertinent to rare disease research. However, if I had to make one suggestion, it would be the inclusion of a topic section that aims to promote engagement with the wider rare disease community. This could be through articles that invite the perspective of patients and stakeholders, such as patient advocacy groups, healthcare policy makers, regulators and leaders in the pharmaceutical industry.
Respectfully Submitted by the Editorial Office
Rare Disease and Orphan Drugs Journal