Pentraxins and amyloidosis: from molecular mechanisms to medicines

We have invented a platform technology for creation of drugs to target any blood protein that causes disease and are using it to develop new medicines.  Our most advanced drug compound targets serum amyloid P component (SAP) and is undergoing clinical testing in amyloidosis, Alzheimer’s disease and osteoarthritis.  It may also be useful in type 2, maturity onset, diabetes.  Other drugs are being designed to treat and prevent hitherto untreatable lethal forms of inherited and acquired amyloidosis.  Our drug which targets C?reactive protein (CRP) is beneficial in rat models of heart attack and stroke, and will be developed for clinical trials.
 
The MRC has funded, continuously since 1979, our research on CRP and SAP, which are related human blood proteins, and our work on amyloidosis, a usually fatal disease.  We study the individual proteins, their interactions with each other and with cells, and animal models of human disease, and we also perform clinical testing in patients.
 
We have introduced new methods of diagnosis and treatment that improve quality and duration of life for most patients who attend the world leading NHS National Amyloidosis Centre in our Department.  We will continue to refine and develop these methods.

We have elucidated much of the molecular pathogenesis, natural history and response to treatment of amyloidosis, as well as the structures and functions of the pentraxins and their roles in disease, but effective therapies are still urgently required. Our discoveries have enabled us to develop a powerful new drug, CPHPC, with a novel pharmacological mechanism of action that both inhibits ligand binding by serum amyloid P component (SAP) and depletes it from the circulation. Clinical testing of CPHPC in amyloidosis is providing promising results, has revealed an unexpected possible application in osteoarthritis, and has informed our rational design of other new drug compounds to target C-reactive protein (CRP) and amyloid fibril precursor proteins. We now aim:
1] to implement this translational research to create new medicines and treatments, including: the continued evaluation and development of CPHPC in systemic amyloidosis; clinical evaluation of CPHPC in Alzheimer?s disease and osteoarthritis; proof of principle demonstration that inhibitors of CRP binding abrogate the tissue damaging effects of human CRP in vivo, opening the way to development of cardioprotective and neuroprotective drugs for clinical use; and continued design, synthesis and experimental evaluation of our novel compounds targeting amyloid fibril precursor proteins, successful outcomes of which will lead swiftly to their clinical development.
2] to continue exploring the roles of pentraxins in health and disease, including: the role of human CRP in experimental murine atherosclerosis and atherothrombosis in vivo, and in human foam cell formation and tissue factor production in vitro; further epidemiological studies of CRP in cardiovascular disease; the role of SAP in the islet amyloid and clinical expression of experimental murine type 2 diabetes; the role of human SAP in the normal glomerular basement membrane and in host defence against Shiga toxins.
3] to vigorously pursue our collaborative studies of the structures of CRP, SAP and their complexes with low molecular weight ligands, peptides, proteins and amyloid fibrils that invaluably subtend all our work on drug design and development as well as providing critical fundamental knowledge of these important molecules.
4] to sustain our very productive and wide ranging clinical research programme on the causes, pathogenesis, diagnosis and treatment of human amyloidosis and the hereditary periodic fever syndromes.