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Prof Sir Mark Pepys
Director, Wolfson Drug Discovery Unit
Centre for Amyloidosis & Acute Phase Proteins
UCL Division of Medicine, Royal Free Campus
London
NW3 2PF
Tel: 020 7433 2801
Fax: 020 7433 2803
Appointment
  • Principal Clinical Research Associate
  • Inflammation
  • Div of Medicine
  • Faculty of Medical Sciences
  • Emeritus Professor of Medicine
  • Div of Medicine
  • Faculty of Medical Sciences
 
 
Biography

Mark Pepys was born in Cape Town, South Africa and came to the UK in 1947. He was educated at Trinity College Cambridge, where he was a Senior Scholar, and took a double first in the Natural Sciences Tripos. After qualifying in medicine at University College Hospital Medical School, he returned to Cambridge for his PhD in immunology and was elected to a Fellowship at Trinity in 1973 in recognition of his discovery of the role of complement in induction of antibody production. After training in clinical medicine and continued immunology research at the Royal Postgraduate Medical School he was appointed Head of the Department of Immunology at the Royal Free Hospital School of Medicine in 1976. In 1977 he returned to the Royal Postgraduate Medical School as Senior Lecturer/Consultant Physician and established the Immunological Medicine Unit, which became one of the world’s leading centres for basic and clinical research on the acute phase response and amyloidosis. He was appointed Professor of Immunological Medicine in 1984. In 1999 he was appointed Professor and Head of the Department of Medicine at the Royal Free Campus of University College London, and moved his whole Department there to establish the UCL Centre for Amyloidosis and Acute Phase Proteins. He also created the UK National Health Service National Amyloidosis Centre, funded by the UK Department of Health to provide diagnostic and management advisory services to the whole national caseload, and which also sees many patients from abroad. His research has been continuously supported by the Medical Research Council since 1969, including a Programme Grant from 1979 to 2009 followed by a Research Grant and the first award under the MRC Developmental Clinical Studies Scheme from 2010-2013 and a second DCS award from 2012-2015. He has also received generous support from the Wolfson Foundation and the Wellcome Trust, including one of the first Seeding Drug Discovery awards from 2007-2010. He is a Fellow of the Royal Society, a Founder Fellow of the Academy of Medical Sciences, and has lately been a member of the Councils of both academies. He was the Harveian Orator of the Royal College of Physicians for 2007 and winner of the Royal Society GlaxoSmithKline Prize in 2007. In 2008 he received the Ernst Chain Prize for medical discovery and in 2009 gave the Annual Keynote Lecture at the Academy of Medical Sciences. In 2011 he retired as Head of Medicine at the Royal Free Campus of UCL in order to become the first Director of the new UCL Wolfson Drug Discovery Unit, created with Wolfson Foundation support and core funding from the NIHR via the UCLH/UCL Biomedical Research Centre. He was created Knight Bachelor for Services to Biomedicine in the 2012 New Year Honours.

Research Summary

After his seminal discovery in 1972 of the role of complement in the induction of antibody production Pepys has mostly worked on amyloid and acute phase proteins. He has illuminated the pathogenesis and natural history of systemic amyloidosis, transforming diagnosis of this fatal disease, and improving management and survival. He has also elucidated the structural properties, function and clinical significance of serum amyloid P component (SAP) and C reactive protein (CRP). He first identified these proteins as therapeutic targets, and has developed new drugs aimed at them.
His invention of in vivo scintigraphy with radiolabelled SAP enabled systemic amyloidosis for the first time to be safely, non invasively diagnosed and quantitatively monitored. This revolutionised understanding of the natural history of amyloidosis and its response to therapy, guiding radical therapeutic developments, especially regarding the crucial importance of reducing the abundance of amyloid fibril protein precursors. Some fatal hereditary amyloidoses are now curable by liver transplantation, and the prognosis of acquired amyloidosis has greatly improved. Pepys has discovered many of the mutations responsible for hereditary amyloidosis, including the first mutations in the human lysozyme gene. He showed that amyloidogenic lysozyme variants are less stable than wild type lysozyme and developed a widely accepted general model of amyloid fibrillogenesis. His detailed phenotypic characterisation of hereditary amyloidoses has improved investigation and management of systemic amyloidosis in general.
Pepys’s first suggestion of small molecule therapy for amyloidosis (1984) led eventually to his novel SAP targeting drug, CPHPC, a bis(D-proline) compound reported in Nature in 2002, which the American Chemical Society recognised as one of the medicinal chemistry annual highlights. This small molecule palindromic ligand cross links pairs of circulating SAP molecules, triggering their immediate clearance from the circulation and depleting SAP from systemic amyloid deposits and from the brain in Alzheimer’s disease. He has demonstrated that the drug may have clinical efficacy in hereditary amyloidosis. The capacity of the drug to deplete SAP from the brain offers an exciting new therapeutic prospect for Alzheimer’s disease, soon to be tested in a clinical trial. His invention of the combination of CPHPC and antibody to serum amyloid P component for treatment of systemic amyloidosis is being developed in collaboration with GlaxoSmithKline and is now being tested in the first patients. GSK are also collaborating on his new small molecule approaches to treatment of transthyretin amyloidosis.
Pepys’s demonstration that CRP increases ischaemic myocardial and cerebral damage in vivo, was the first validation of CRP as a potential therapeutic target. His success in targeting SAP enabled his rational design of bis phosphocholine hexane, the first specific inhibitor of CRP, reported in Nature in 2006. Development of more medicinal CRP inhibitor compounds for treatment of conditions associated with greatly increased CRP production is in progress with MRC support. Pepys previously played a leading role in establishing the routine use of CRP testing in clinical practice, and produced the WHO International Immunoassay Reference Standards for CRP, serum amyloid A protein, and thyroxine binding globulin.

Appointments
1999 – 2011 Professor of Medicine and Head Medicine University College London, United Kingdom
1999 – 2011 Director, Centre for Amyloidosis & Acute Phase Proteins Medicine University College London, United Kingdom
1984 – 1999 Professor Immunological Medicine RPMS/ICSM, Hammersmith Hospital, United Kingdom
1980 – 1984 Reader Immunological Medicine RPMS, Hammersmith Hospital, United Kingdom
1977 – 1999 Consultant Physician   Hammersmith Hospital, United Kingdom
1977 – 1980 Senior Lecturer Medicine RPMS, Hammersmith Hospital, United Kingdom
1976 – 1977 Senior Lecturer and Head Immunology Royal Free Hospital School of Medicine, United Kingdom
1974 – 1976 Assistant Lecturer/Honorary Senior Registrar   RPMS, Hammersmith Hospital, United Kingdom
1973 – 1974 Medical Registrar   RPMS, Hammersmith Hospital, United Kingdom
1973 – 1979 Fellow   Trinity College, Cambridge, United Kingdom
1970 – 1970 Research Assistant/Honorary Registrar   RPMS, Hammersmith Hospital, United Kingdom
1970 – 1973 Research Scholar   Trinity College, Cambridge, United Kingdom
1970 – 1973 MRC Junior Research Fellow   University of Cambridge, United Kingdom
1969 – 1970 Senior House Officer   RPMS, Hammersmith Hospital, United Kingdom
1969 – 1969 House Surgeon   University College Hospital, United Kingdom
1968 – 1969 House Physician   University College London, United Kingdom
Academic Background
1998 FMedSci Fellow of the Academy of Medical Sciences Academy of Medical Sciences
1998 FRS Fellow of the Royal Society Royal Society
1991 FRCPath Fellow of the Royal College of Pathologists Royal College of Pathologists, UK
1982 MD Doctor of Medicine University of Cambridge
1981 FRCP Fellow of the Royal College of Physicians Royal College of Physicians
1981 MRCPath Member of the Royal College of Pathologists Royal College of Pathologists, UK
1974 PhD Doctor of Philosophy University of Cambridge
1970 MA Master of Arts University of Cambridge
1970 MRCP Member of the Royal College of Physicians Royal College of Physicians
1968 MB BChir Bachelor of Medicine/ Bachelor of Surgery University of Cambridge
1965 BA Hons Bachelor of Arts (Honours) University of Cambridge
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