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.

Our world-leading research covers all aspects of the pentraxin family of plasma proteins and amyloidosis. Our studies range from molecular, genetic, biochemical, physiological, and pathological investigations to clinical diagnostics, patient management and new drug discovery.

We also investigate inflammatory diseases and the major common diseases associated with local amyloid deposits: Alzheimer's disease and type 2 diabetes mellitus.

Amyloid and amyloidosis

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 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. This leads 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. 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). We have worked for over 40 years on this and related proteins belonging to 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. 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).

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 three years.

C-reactive protein

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.

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 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.

Professors, Readers, Lecturers and Consultants

Selected publications

1. Fontana M, Solomon SD, Kachadourian J, Walsh L, Rocha R, Lebwohl D, Smith D, Täubel J, Gane EJ, Pilebro B, Adams D, Razvi Y, Olbertz J, Haagensen A, Zhu P, Xu Y, Leung A, Sonderfan A, Gutstein DE, Gillmore JD. CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy. N Engl J Med. 2024 Nov 16.
2. Fontana M, Berk JL, Gillmore JD, Witteles RM, Grogan M, Drachman B, Damy T, Garcia-Pavia P, Taubel J, Solomon SD, Sheikh FH, Tahara N, González-Costello J, Tsujita K, Morbach C, Pozsonyi Z, Petrie MC, Delgado D, Van der Meer P, Jabbour A, Bondue A, Kim D, Azevedo O, Hvitfeldt Poulsen S, Yilmaz A, Jankowska EA, Algalarrondo V, Slugg A, Garg PP, Boyle KL, Yureneva E, Silliman N, Yang L, Chen J, Eraly SA, Vest J, Maurer MS; HELIOS-B Trial Investigators. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med. 2024 Aug 30.
3. Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia P, Gibbs S, Grogan M, Hanna M, Hoffman J, Masri A, Maurer MS, Nativi-Nicolau J, Obici L, Poulsen SH, Rockhold F, Shah KB, Soman P, Garg J, Chiswell K, Xu H, Cao X, Lystig T, Sinha U, Fox JC; ATTRibute-CM Investigators. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2024 Jan 11;390(2): 132-142.
4. Maurer MS, Kale P, Fontana M, Berk JL, Grogan M, Gustafsson F, Hung RR, Gottlieb RL, Damy T, González-Duarte A, Sarswat N, Sekijima Y, Tahara N, Taylor MS, Kubanek M, Donal E, Palecek T, Tsujita K, Tang WHW, Yu WC, Obici L, Simões M, Fernandes F, Poulsen SH, Diemberger I, Perfetto F, Solomon SD, Di Carli M, Badri P, White MT, Chen J, Yureneva E, Sweetser MT, Jay PY, Garg PP, Vest J, Gillmore JD; APOLLO-B Trial Investigators. Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis. N Engl J Med. 2023 Oct 26;389(17): 1553-1565.
5. Fontana M, Gilbertson J, Verona G, Riefolo M, Slamova I, Leone O, Rowczenio D, Botcher N, Ioannou A, Patel RK, Razvi Y, Martinez-Naharro A, Whelan CJ, Venneri L, Duhlin A, Canetti D, Ellmerich S, Moon JC, Kellman P, Al-Shawi R, McCoy L, Simons JP, Hawkins PN, Gillmore JD. Antibody-Associated Reversal of ATTR Amyloidosis-Related Cardiomyopathy. N Engl J Med. 2023 Jun 8;388(23): 2199-2201.
6. Judge DP, Gillmore JD, Alexander KM, Ambardekar AV, Cappelli F, Fontana M, García-Pavía P, Grodin JL, Grogan M, Hanna M, Masri A, Nativi-Nicolau J, Obici L, Hvitfeldt Poulsen S, Sarswat N, Shah K, Soman P, Lystig T, Cao X, Wang K, Pecoraro ML, Tamby JF, Katz L, Sinha U, Fox JC, Maurer MS. Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial. Circulation. 2024 Nov 18.
7. Porcari A, Cappelli F, Nitsche C, Tomasoni D, Sinigiani G, Longhi S, Bordignon L, Masri A, Serenelli M, Urey M, Musumeci B, Cipriani A, Canepa M, Badr-Eslam R, Kronberger C, Chimenti C, Zampieri M, Allegro V, Razvi Y, Patel R, Ioannou A, Rauf MU, Petrie A, Whelan C, Emdin M, Metra M, Merlo M, Sinagra G, Hawkins PN, Solomon SD, Gillmore JD, Fontana M. SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2024 Jun 18;83(24): 2411-2422.
8. Ioannou A, Cappelli F, Emdin M, Nitsche C, Longhi S, Masri A, Cipriani A, Zampieri M, Colio F, Poledniczek M, Porcari A, Razvi Y, Aimo A, Vergaro G, De Michieli L, Rauf MU, Patel RK, Villanueva E, Lustig Y, Venneri L, Martinez-Naharro A, Lachmann H, Wechalekar A, Whelan C, Petrie A, Hawkins PN, Solomon S, Gillmore JD, Fontana M. Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis. J Am Coll Cardiol. 2024 Mar 1;83(14): 1276-91.
9. Patel RK, Bandera F, Venneri L, Porcari A, Razvi Y, Ioannou A, Chacko L, Martinez-Naharro A, Rauf MU, Knight D, Brown J, Petrie A, Wechalekar A, Whelan C, Lachmann H, Muthurangu V, Guazzi M, Hawkins PN, Gillmore JD, Fontana M. Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis. JAMA Cardiol. 2024 Apr 1;9(4): 367-376.
10. Porcari A, Fontana M, Canepa M, Biagini E, Cappelli F, Gagliardi C, Longhi S, Pagura L, Tini G, Dore F, Bonfiglioli R, Bauckneht M, Miceli A, Girardi F, Martini AL, Barbati G, Costanzo EN, Caponetti AG, Paccagnella A, Sguazzotti M, La Malfa G, Zampieri M, Sciagrà R, Perfetto F, Rowczenio D, Gilbertson J, Hutt DF, Hawkins PN, Rapezzi C, Merlo M, Sinagra G, Gillmore JD. Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy. Circulation. 2024 Apr 9;149(15): 1157-1168.

Funding and partnerships

Our research on amyloidosis and pentraxins received over £18 million from the Medical Research Council between 1969-2016, the longest continuous MRC support to an external researcher (Professor Sir Mark Pepys).

We have received substantial support from The Wolfson Foundation (almost £4 million), The Wellcome Trust (including a £3.8 million Seeding Drug Discovery Initiative Award) and other medical charities. Between 2012 and 2022, core support for the Wolfson Drug Discovery Unit was provided by the NIHR via the UCLH/UCL BRC.

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.

Awards

• 2007 - Professor Pepys awarded the Royal Society's GlaxoSmithKline Prize and Lecture.
• 2008 - Professor Pepys awarded the Ernst Chain Prize.
• 2012 - Professor Pepys receives a knighthood for services to biomedicine.

Support us

Charitable donations from patients, relatives and other supporters of research and patient care enable crucial developments that benefit patients. Our cutting-edge research requires access to sophisticated new equipment and highly qualified staff.

Donations are now collected by the Royal Free Charity. Fund 24 is dedicated to the NAC. A generous donor has also pledged to match all donations to the fund until the total reaches £500,000, so your donations will be doubled until this total is reached.

Your support will make major inroads to easing the suffering and saving the lives of many thousands of individuals afflicted by a terrible and hitherto incurable disease. Every gift of any size will make a real difference.

Make a donation

Fundraise for us