Organiser's Note: The presenter of this talk withheld their permission for video to be published.
Amyloidosis is disease caused by extracellular deposition of amyloid. The deposits are composed of amyloid fibrils, proteoglycans and serum amyloid P component (SAP), a normal non-fibrillar plasma glycoprotein. About 25 different unrelated proteins are known to form amyloid fibrils in vivo in different conditions but the fibrils all share a common cross beta core structure derived by misfolding and then aggregation of their globular precursors. Systemic amyloidosis, with major deposits affecting the viscera, blood vessels and connective tissue, is always fatal and causes about one per thousand of all deaths in developed countries. Microscopic amyloid deposits are also always present in aged individuals but their clinical significance is unknown. Amyloid deposits are also always present in the brain in Alzheimer's disease and in the pancreatic islets in type 2 diabetes but the contribution, if any, of amyloid to pathogenesis is not known. There are many other disease associated with protein misfolding but these are not amyloidoses.
Systemic amyloidosis is a major unmet medical need and new treatments to prevent amyloid deposition and promote amyloid clearance are urgently required. If such approaches are effective their deployment in Alzheimer's disease and type 2 diabetes will be of considerable interest. We have developed novel therapies for systemic amyloidosis and report here on their current status. (R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) is a palindromic bis(D proline) which is bound by circulating SAP and causes its rapid and almost complete depletion, thereby also depleting most but not all SAP from amyloid deposits. Continuous treatment of systemic amyloidosis patients with CPHPC produces sustained SAP depletion, arrests new amyloid accumulation and stabilises function of amyloidotic organs but does not trigger amyloid regression. Administration of CPHPC in patients with Alzheimer's disease depletes SAP completely from the CSF as well as the blood and we are working towards a phase 2 clinical trial in this condition.
In the mouse model of systemic AA amyloidosis in human SAP transgenic mice, administration of CPHPC to clear circulating SAP followed by a single dose of anti-SAP antibody causes rapid and virtually complete clearance of massive visceral amyloid deposits via a complement and macrophage dependent mechanism. This combination approach is now in full scale development, in collaboration with GlaxoSmithKline, for clinical testing during 2011.
We have invented new chemical entities targeting transthyretin, the amyloid fibril protein in senile cardiac amyloidosis and hereditary systemic transthyretin amyloidosis (familial amyloid polyneuropathy), and are developing these towards clinical testing with the support of a Wellcome Trust Seeding Drug Discovery Initiative award.