Research

Contribution to Science, Research
and Public Engagements

Dr. Michel has played a major role in improving the quality, depth and breadth of scientific, medical and research information patients with inherited eye disease can access by providing first class text and images for the website of Retina UK. This is the primary source of information for patients in the UK with inherited retinal dystrophies and received over 4 million hits in 2018 – suggesting a far wider audience.

His focus now is on the development and validation of clinical trial endpoints to accelerate the process of testing novel therapies.

This aforementioned body of work has improved advice on prognosis and genetic counselling, identified the underlying molecular genetic basis of multiple isolated and syndromic disorders, shed light on mechanisms of disease, identified potential novel therapeutic targets, and provided data that will be invaluable for current and future therapeutic interventions.

It is worth mentioning that he has over 300 peer-reviewed publications and 30 authored book chapters; with over 400 publications since 2010, and over 20,000 citations in total. A list of his peer-reviewed Publications can be found here.

Research Funding Organisations

Contributions to Science

Prof. Michel has been integral to UCL Institute of Ophthalmology’s (IOO) and Moorfields Eye Hospital’s (MEH) significant on-going contribution to the understanding of inherited retinal degenerative diseases and diabetic eye disease over the last 20 years, in terms of:

Clinical characterisation, genotype-phenotype correlations, and structure-function associations

Detailed phenotyping in multiple patient groups including:

• The stationary cone dysfunction syndromes (Achromatopsia, Blue Cone Monochromatism, Oligocone Trichromacy, X-linked Cone Dysfunction Syndrome associated with Myopia and Dichromacy, and Bradyopsia)
• Progressive cone dystrophies (cone dystrophy (COD) with supernormal rod ERG, and cone dystrophies associated with mutation in CNGB3 and GUCA1A)
• Cone-rod dystrophies (CORDs) (an autosomal dominant cone-rod dystrophy (CORD7), a syndrome of CORD with amelogenesis imperfecta, enhanced S-cone syndrome (ESCS), and CORD associated with the p.R172W PRPH2)
• Central receptor dystrophies (multiple macular dystrophy phenotypes including Stargardt Disease)
• Progressive rod-cone dystrophies (Leber Congenital Amaurosis, Retinitis Pigmentosa, and Posterior Column Ataxia and Retinitis Pigmentosa (PCARP)).

These studies have resulted in a more detailed description of the phenotype, including establishing/refining the clinical characteristics, phenotypic variability, and natural history. Illustrated by:

A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations.

Fujinami K, Lois N, Davidson AE, Mackay DS, Hogg CR, Stone EM, Tsunoda K, Tsubota K, Bunce C, Robson AG, Moore AT, Webster AR, Holder GE, Michaelides M. Am J Ophthalmol. 2013;155(6):1075-1088.

This is the first longitudinal study of electrophysiological function in Stargardt Disease, which has had major direct impact on advice on prognosis, genetic counseling and planning for clinical trials for the commonest inherited macular dystrophy.

Advanced high-resolution quantitative retinal imaging and prospective natural history studies

The aforementioned 3 research areas in (1) have provided a better understanding of these inherited retinal diseases and also highlighted the need for my on-going area of interest, namely the prospective investigation of natural history and progression (including being the UK PI on an international multi-centre natural history study for Stargardt disease) and the application of high-resolution quantitative retinal imaging to better determine the cellular phenotype, resulting in further novel insights pertaining to disease mechanisms and moreover facilitating the preparation for therapeutic interventions by developing improved clinical trial design and metrics. Illustrated by following studied diseases:

• The stationary cone dysfunction syndromes – Achromatopsia, Blue Cone Monochromatism, Oligocone Trichromacy, & X-linked Cone Dysfunction Syndrome associated with Myopia and Dichromacy. Illustrated by:
  • Retinal Structure and Function in Achromatopsia: Implications for Gene Therapy.
    Sundaram V, Wilde C, Aboshiha J, Cowing J, Han C, Langlo CS, Chana R, Davidson AE, Sergouniotis PI, Bainbridge JW, Ali RR, Dubra A, Rubin G, Webster AR, Moore AT, Nardini M, Carroll J, Michaelides M. Ophthalmology 2014;121(1):234-45
    Application of in-depth phenotyping defining the window of opportunity and patient selection criteria, with direct relevance to our on-going gene therapy trial, and for other groups around the world developing similar interventions
  • The effect of cone opsin mutations on retinal structure and the integrity of the photoreceptor mosaic. Carroll J, Dubra A, Gardner JC, Mizrahi-Meissonnier L, Cooper RF, Dubis AM, Nordgren R, Genead M, Connor TB Jr, Stepien KE, Sharon D, Hunt DM, Banin E, Hardcastle AJ, Moore AT, Williams DR, Fishman G, Neitz J, Neitz M, Michaelides M. Invest Ophthalmol Vis Sci. 2012;53(13):8006-15.
    The application of in-depth advanced phenotyping, including high-resolution quantitative retinal imaging with OCT and AOSLO to improve understanding of disease mechanisms, natural history, genotype-phenotype correlations, and provide evidence suggesting gene replacement therapy is a viable option
• Stargardt Disease
• Progressive rod-cone dystrophies (Leber Congenital Amaurosis associated with RPE65 and AIPL1, and X-linked Retinitis Pigmentosa associated with RPGR)

Underlying molecular genetics both in terms of identification of novel genes and also characterising the mutation spectrum and prevalence in known genes

• Characterising the mutation spectrum and prevalence in known genes:
  • Achromatopsia (CNGA3, CNGB3, GNAT2, PDE6C, ATF6)
  • Blue Cone Monochromatism (OPN1LW/OPN1MW)
  • Bradyopsia (RGS9, R9AP)
  • ESCS (NR2E3)
  • COD/CORD (RPGR, GUCA1A, PRPH2, KCNV2)
  • Macular Dystrophies (PRPH2, ABCA4, A3243G mtDNA, EFEMP1, RP1L1)
  • LCA (RPE65, AIPL1, GUCY2D).
• The identification of novel genes, including:
  • A. Novel genes causing:
    • Achromatopsia (GNAT2, ATF6)
    • Progressive COD (CNGB3 and OPN1LW/OPN1MW)
    • Congenital stationary night blindness (TRPM1)
    • Retinitis Pigmentosa (RP1L1)
  • B. The underlying molecular genetic basis has been established in:
    • COD with supernormal rod ERG (KCNV2),
    • A dominant macular dystrophy (MCDR2) (PROM1)
    • The CORD syndrome associated with amelogenesis imperfecta (CNNM4)
    • PCARP (FLVCR1)
    • X-linked cone dysfunction syndrome associated with myopia and dichromacy (Bornholm Eye Disease)(OPN1LW/OPN1MW)

Notable contributions to the literature relating to the management of diabetic macular oedema and proliferative diabetic retinopathy, which have informed clinical practice

• A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study): 12-Month Data Report 2.
  Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG. Ophthalmology 2010;117:1078-1086.
  Dr. Michel’s most cited publication – cited by 557. Worldwide impact on the clinical management of one of the commonest causes of acquired retinal blindness in the developed world.
• The Effect of Multispot Laser Panretinal Photocoagulation on Retinal Sensitivity and Driving Eligibility in Patients With Diabetic Retinopathy.
  Subash M, Comyn O, Samy A, Qatarneh D, Antonakis S, Mehat M, Tee J, Mansour T, Xing W, Bunce C, Viswanathan A, Rubin G, Weleber R, Peto T, Wickham L, Michaelides M. JAMA Ophthalmol. 2016;134(6):666-72.
  A prospective study of novel laser therapy effect on retinal sensitivity and driving eligibility in diabetic retinopathy. Worldwide impact on counselling and clinical management of one of the commonest causes of severe visual loss.

Enabling and Leadership

1. Public Engagement (PE) – Patient Days for Age-related Macular Degeneration (2014), Retina (2015), and Stargardt Disease (2017). Faculty of Brain Sciences awarded the Communications Excellence award in PE to Retina Day (2015).
2. Lead live webchat during MEH Rare Disease Day (2016).
3. Invited by the NIHR Horizon Scanning Centre to provide expert input into a review on new and emerging technologies for inherited retinal diseases. This has been published by the NIHR (2014) and a manuscript published in the journal of the Royal College of Ophthalmologists, EYE (2015).
4. On-going provision of updated medical and research information for the Retina UK website since 2010 (4 million hits in 2018; suggesting a far wider audience) and helped to establish and inform the first standalone website for Stargardt Disease (2018). Also provided text and advice for the websites of Fight for Sight, the Macular Society, and the Royal Society for Blind Children (2016-2020).
5. Participation in both the (i) Paediatric and (ii) Ophthalmology domains in the Genomics England Clinical Interpretation Partnership.
6. Peer review for journals (Eye, British Journal of Ophthalmology, Acta Ophthalmologica, Retina, American Journal of Ophthalmology, Prog Retin Eye Res, Ophthalmology, Ophthalmology Retina, and Investigative Ophthalmology & Visual Science).
7. Peer review grants for national and international awarding bodies, including The Guide Dogs for the Blind Association, NIHR, Wellcome Trust, Medical Research Council, National Eye Research Centre, The Netherlands Organisation for Health Research and Development Rare Diseases Programme, The Ophthalmic Research Institute of Australia, Foundation Fighting Blindness (USA), and Fondazione Roma.
8. Invited by Director of the Wellcome Trust to be a Therapeutic Expert (Ophthalmology) to assist the Independent review panel for ClinicalStudyDataRequest.com