Wellcome Trust Centre For Mitochondrial Research

Dr Patrick Yu-Wai-Man

Biography

patrick 2I am an academic ophthalmologist with a specialist research interest in mitochondrial eye disorders. My aim is to understand why the eye is selectively vulnerable in mitochondrial disease and how we can best manage patients with these problems. A major objective of my work is how we can translate the knowledge gained in the lab into more effective treatment strategies for this group of patients.

As a Newcastle medical undergraduate, I intercalated one year of research with Patrick Chinnery and Doug Turnbull (2000-2001). The aim of my BMedSci project was to clarify the molecular genetics of Leber hereditary optic neuropathy (LHON), a complex mitochondrial disorder that causes blindness in young adults. It was an exciting time at the cutting edge of lab research and it got me hooked onto the field of mitochondrial eye disease. My research group is based at the Institute of Genetic Medicine (Centre for Life) where I work closely with my two colleagues Patrick Chinnery and Rita Horvath.

I contribute to the clinical service of patients with mitochondrial disease in Newcastle with other members of the Mitochondrial Research Group. In addition to my Newcastle activities, I run a specialist optic nerve genetics clinic at Moorfields Eye Hospital. I also work closely with my research colleagues based at the UCL Institute of Ophthalmology as part of a strategic collaboration between the Newcastle and Moorfields NIHR Biomedical Research Centres.

Qualifications
2015    FRCPath Royal College of Pathologists (UK)
2012    FRCOphth Royal College of Ophthalmologists (UK)
2010    PhD  Newcastle University
2005    MRCOphth Royal College of Ophthalmologists (UK)
2002    MBBS (Honours with distinction) Newcastle University
2001    BMedSci (First class honours)  Newcastle University

Current Appointments

  • Honorary Consultant Ophthalmologist Moorfields Eye Hospital, London.
  • Clinical Senior Lecturer (Tenured) Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University.
  • Medical Research Council (MRC) Clinician Scientist Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University.
  • Honorary Consultant Neuro-Ophthalmologist Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne.
  • Honorary Clinical Senior Lecturer NIHR Biomedical Research Centre, UCL Institute of Ophthalmology, London.

Publications

Research Project

Principal Investigators Patrick Yu-Wai-Man
I am an academic ophthalmologist with a specialist research interest in mitochondrial eye disorders. My aim is to understand why the eye is selectively vulnerable in mitochondrial disease and how we can best manage patients with these problems. A major objective of my work is how we can translate the knowledge gained in the lab into more effective treatment strategies for this group of patients.

(1) Diagnosis
Reaching a diagnosis for relatively rare mitochondrial disorders is not always straightforward. Examining the eye can provide important clues and these can point scientists in the right direction what to look for in the lab. I also look after families who do not yet have a confirmed diagnosis and we are applying next-generation sequencing technologies to try and identify the underlying genetic cause.

(2) Prognosis
Some patients with mitochondrial disease only develop eye problems, whereas others, sometimes from the same family, experience more widespread problems affecting the brain, skeletal muscle and peripheral nerves. By following these patients long term, our aim is to identify biomarkers that could help predict the course of the disease and the reasons for this marked variability. The eye has the great advantage that it can be directly visualised and we are collecting additional information on our patient cohort using sophisticated high-resolution imaging techniques.

(3) Treatment
Treatment for mitochondrial eye disorders is currently mostly supportive and it is very frustrating for clinicians and patients alike. A major objective of my research work is how we can prevent further visual loss in patients with LHON and DOA. We recently conducted a multicentre double-blind randomised placebo-controlled trial to investigate the efficacy of high-dose oral idebenone in LHON (http://www.ncl.ac.uk/press.office/press.release/item/drug-shown-to-improve-sight-for-patients-with-inherited-blindness). These results are encouraging and further work is currently ongoing to look into idebenone and other neuroprotective agents more closely. The eye also represents the perfect organ for gene therapy as it is easily accessible for the injection of the viral replacement vector.

Staff Profile

Ophthalmology Research Links

Contact Details
E-Mail: Patrick.Yu-Wai-Man@ncl.ac.uk
Institute of Genetic Medicine, Newcastle University
Newcastle upon Tyne, NE1 3BZ, United Kingdom
Tel:  +44(0)191 241 8854
Fax: +44(0)191 241 8666

Newcastle Eye Centre, Royal Victoria Infirmary
Newcastle upon Tyne, NE1 4LP, United Kingdom
Tel:  +44(0)191 282 5447
Fax: +44(0)191 282 5446

Sponsor/Funder
2017 – 2020    MRC (UK)      DPFS Grant – TREAT WOLFRAM (£2M)
2016 – 2019    NIHR (UK)    Industry Collaboration Grant (£310K)
2014 – 2017    NIHR (UK)    Rare Disease Translational Project Grant (£248K)
2012 – 2016    MRC (UK)      Clinician Scientist Fellowship (£898K)
2008 – 2011    MRC (UK)      Clinical Research Training Fellowship (£197K)

Collaborators
Professor Marcela Votruba (Cardiff, UK)
Professor Joanna Poulton (Oxford, UK)
Professor Timothy Barrett (Birmingham, UK)
Dr Valerio Carelli (Bologna, Italy)
Dr Piero Barboni (Bologna, Italy)
Dr Guy Lenaers (Montpellier, France)
Dr Patrizia Amati-Bonneau (Angers, France)
Dr Veronique Paquis-Flucklinger (Nice, France)
Professor Alfredo Sadun (Los Angeles, USA)
Professor Nancy Newman (Atlanta, USA)

Outcomes
Selected Publications:

  1. Rouzier C, Moore D, Delorme C, Lacas-Gervais S, Ait-El-Mkadem S, Fragaki K, Burté F, Serre V, Bannwarth S, Chaussenot A, Catala M, Yu-Wai-Man P**, Paquis-Flucklinger V**. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Human Molecular Genetics. 2017;26:1599-1611.
  2. Spiegel R, Saada A, Flannery PJ, Burté F, Soiferman D, Khayat M, Eisner V, Vladovski E, Taylor RW, Bindoff LA, Shaag A, Mandel H, Furman O, Shalev SA, Elpeleg O, Yu-Wai-Man P. Fatal infantile mitochondrial encephalomyopathy and hypertrophic cardiomyopathy associated with a homozygous OPA1 Journal of Medical Genetics. 2016;53:127-31.
  3. Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathologica. 2016;132:789-806.
  4. Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nature Reviews Neurology. 2015;11:11-24.
  5. Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies – past, present and future. Eye. 2014;28:521-537.
  6. Pfeffer G, Burke A, Yu-Wai-Man P, et al. The clinical features of multiple sclerosis associated with Leber hereditary optic neuropathy mtDNA mutations. Neurology. 2013;81:2073-2081.
  7. Klopstock K, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677-2686.
  8. Yu-Wai-Man P, Griffiths PG, Gorman GS, et al. Multi-system neurological disease is common in patients with OPA1 Brain. 2010;133:771-786.
  9. Greaves LC, Yu-Wai-Man P, Blakely EL, et al. Mitochondrial DNA defects and selective extraocular muscle involvement in chronic progressive external ophthalmoplegia. Investigative Ophthalmology and Visual Science. 2010;51:3340-3346.
  10. Yu-Wai-Man P, Sitarz KS, Samuels DC, et al. OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules. Human Molecular Genetics. 2010;19:3043-3052.

Clinical Trials:
2016 –             LHON gene therapy trials (RESCUE and REVERSE)
2016 –             Efficacy and safety of idebenone in LHON (LEROS)
2007 – 2010  Rescue of Hereditary Optic Disease Outpatient Study (RHODOS)