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 30 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.
Our new approach to removal
of amyloid deposits in patients with systemic amyloidosis is described below.
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 have developed a new drug (CPHPC) that specifically
targets SAP and depletes it from the blood and tissues. Our initial
studies suggest that the drug may be of benefit in some patients with systemic
amyloidosis but it does not lead, as was hoped, to regression of amyloid
deposits from the tissues.
In 2005 Pepys invented a new approach using
CPHPC to deplete SAP from the blood but 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 clinical trial started in June 2013 and
its successful results in patients with systemic amyloidosis have been
published in the New England Journal of Medicine (Richards
DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM,
Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys
MB. Therapeutic clearance of amyloid by antibodies to serum amyloid P
component. N Engl J Med 2015;373:1106-14) and in Blood (Pepys MB,
Cookson LM, Barton SV, Berges AC, Lane T, Hutt D, Fontana M,
Moon JC, Gillmore JD, Wechalekar W, Hawkins PN, Richards DB. Dose-dependent progressive immunotherapeutic clearance of systemic
amyloid deposits by repeated doses of antibody to serum amyloid P component
(SAP). Blood 2015;126:1836).
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 Lowe GDO & Pepys MB. C-reactive protein and cardiovascular disease: weighing the evidence. Curr Atheroscler Rep 2006;8:421-8 and Casas JP, Shah T, Hingorani AD, Danesh J, Pepys MB. C-reactive protein and coronary heart disease: a critical review. J Int Med 2008;264:295-314). 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 (Lane T, Wassef N, Poole S, Mistry Y, Lachmann HJ, Gillmore JD, Hawkins PN, Pepys MB. Infusion of pharmaceutical‑grade natural human C‑reactive protein is not pro‑inflammatory in healthy adult human volunteers. Circ Res 2014;114:672-6).
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 a 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 (Simons
JP, Loeffler JM, Al-Shawi R, Ellmerich S, Hutchinson WL,
Tennent GA, Petrie A, Raynes JG, de Souza JB, Lawrence
RA, Read KD, Pepys MB. C-reactive protein is essential for
innate resistance to pneumococcal infection. Immunology, 2014;142:414-20).
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.
We have also received substantial support
from The Wolfson Foundation (totalling £3.5 million), The Wellcome Trust
(including a £3.8 million Seeding Drug Discovery Initiative Award) and other
donations by patients and their relatives and friends to the UCL Amyloidosis
Research Fund, within the umbrella of the UCL Development Fund, provide
flexible non-earmarked resources which are immensely helpful to our fast moving
Since 2012 core support for the Wolfson Drug Discovery Unit has been provided by the NIHR via the UCLH/UCL Biomedical Research Centre.