Amyloid and amyloidosis
Amyloidosis is a disorder of protein folding in which normally soluble proteins accumulate in the tissues as abnormal insoluble fibrils. These deposits damage the structure and function of the tissues and cause serious disease which is usually fatal if it affects major organs.
Amyloid deposition in the brain is always present in Alzheimer's disease but it is not known whether the amyloid itself causes dementia. Similarly, amyloid deposits are universally present in the pancreas in maturity onset diabetes and may be related to islet failure. Our team has worked on many aspects of these diseases for 40 years, and continues to elucidate fundamental molecular and pathogenetic mechanisms, develop new diagnostic procedures and introduce new and improved approaches to treatment, leading to greatly prolonged patient survival.
Our clinical service in systemic amyloidosis has been recognised and comprehensively funded directly by the UK Department of Health as the UK National Health Service National Amyloidosis Centre since 1999, with Professor Philip Hawkins as Clinical Director. The Centre provides diagnostic and management advisory services for the whole national caseload and many patients from Europe and elsewhere around the world.
Pentraxins and the acute phase response
The acute phase response is a complex adaptive response to most forms of tissue injury, infection and inflammation, that is conserved amongst all endothermic species and is characterised by increased production and circulating concentrations of a range of different plasma proteins.
The first such acute phase protein to be identified was C-reactive protein (CRP) and we have worked for more than 40 years on this and related proteins belonging to what is known as the pentraxin family. The other human pentraxin is serum amyloid P component (SAP), which is a universal constituent of amyloid deposits and contributes to their pathogenesis. We developed a new drug, miridesap (formerly known as CPHPC) that specifically targets SAP and depletes it from the blood and reduces the amount of SAP in amyloid deposits within the tissues. However, it does not remove all the amyloid bound SAP and this observation led Professor Sir Mark Pepys to a new therapeutic invention in 2005.
Targeting serum amyloid P component (SAP)
Pepys used miridesap to deplete SAP from the blood while leaving some SAP in the amyloid deposits. Antibodies to SAP can then be given safely and they target the amyloid deposits for destruction and clearance by macrophages, the professional debris-clearing cells of the body. This treatment dramatically clears established visceral amyloid deposits in experimental models and in 2009 it was licensed to GlaxoSmithKline for a collaborative development programme. The first in human clinical trial started in June 2013 and produced unprecedented, safe and effective removal of visceral amyloid deposits in patients with systemic amyloidosis. The results have been published in the N Engl J Med (2015) and Sci Transl Med (2018). Unfortunately GSK subsequently decided that the risk benefit profile of this treatment was unfavourable and terminated development in 2018. Nevertheless, compelling proof of concept has been achieved, showing that antibody treatment can remove amyloid from the tissues with clinical benefit, and Pepys is continuing to design and develop immunotherapy for amyloidosis.
The DEpletion of Serum Amyloid P Component In Alzheimer's Disease (DESPIAD) phase 2b clinical trial of miridesap (CPHPC), which depletes serum amyloid P component from the brain (Proc Natl Acad Sci USA 2009; Open Biol 2016) is being conducted in the Leonard Wolfson Experimental Neurology Centre at the UCL Institute of Neurology. It is sponsored by UCL and funded by the NIHR via the UCLH/UCL BRC with additional support from Alzheimer's Research UK and the Dana Foundation of New York. Professor Martin Rossor FMedSci, the NIHR National Director for Dementia Research, and Professor Sir Mark Pepys FRS FMedSci are the principal investigators. The trial started in September 2018 and will run for at least 3 years.
We have made many contributions to knowledge of the structure, function and clinical applications of C-reactive protein (CRP), including the very topical area of CRP measurement in cardiovascular disease (reviewed in Curr Atheroscler Rep 2006 and J Int Med 2008). Claims that human CRP is itself inherently pro‑inflammatory have been extremely controversial. Despite experimental studies purporting to support this view it was always inconsistent with abundant clinical observations. In order to resolve the matter we isolated a unique preparation of cGMP, pharmaceutical grade, human CRP from normal donor plasma. Intravenous infusion of substantial doses of this material into healthy volunteers had absolutely no pro-inflammatory, or indeed any other effects, apart from raising the plasma concentration of CRP in a dose dependent fashion (Circ Res 2014).
Another area of controversy has been the normal function of CRP in vivo. Despite many assertions about this, there is no compelling evidence in humans, because no deficiency or variant of CRP has ever been reported and there is no drug or other intervention that specifically ablates human CRP in vivo. We explored this question in pre-clinical studies and demonstrated clearly that CRP is responsible for protection against infection by a particular type of bacterium, the pneumococcus, which is a common cause of pneumonia and meningitis. It is thus very likely that this is a major function of human CRP and explains why the protein is always present and is invariant (Immunology 2014).
Meanwhile, we have proved that when there is pre-existing tissue damage, increased CRP production can exacerbate the damage (J Exp Med 1999) and we then designed small molecule CRP inhibitors compounds to abrogate this effect (Nature 2006). The original compounds proved not to be developable as drugs but we are now well on the way towards design of more pharmaceutical compounds and the eventual development of an effective CRP inhibitor drug in a programme funded by Apollo Therapeutics.
After initial grants from the Medical Research Council starting in 1969, our work on amyloidosis and pentraxins was funded from 1979-2009 by a Medical Research Council Programme Grant to Professor Sir Mark Pepys. Additional MRC support continued until 2016, making Pepys’s funding of more than £18 million from 1969-2016 the longest continuous MRC support to an external researcher.
We have also received substantial support from The Wolfson Foundation (totalling nearly £4 million), The Wellcome Trust (including a £3.8 million Seeding Drug Discovery Initiative Award) and other medical charities.
Generous charitable donations by patients and their relatives and friends to the Amyloidosis Research Fund provides flexible non-earmarked resources which are immensely helpful to our fast moving research programmes.
Since 2012 core support for the Wolfson Drug Discovery Unit has been provided by the NIHR via the UCLH/UCL BRC and currently extends to 2022.