Amyloidosis is a disorder of protein folding, in which a normal soluble protein is deposited in extracellular tissue spaces. Amyloidosis has been proposed as a pathogenic mechanism associated with neurodegeneration in Alzheimer disease, with islet failure in type 2 diabetes and is also a common complication of hemodialysis for end-stage renal failure.
Although there is still no definitive evidence that accumulation of amyloid is causal for these diseases, it is believed that removal of amyloid may have a clinical effect.
Recently, a compound has been identified that may allow for breakdown of amyloid deposits. A series of experiments were designed to investigate the role of a serum amyloid P component, or SAP, protein in amyloid deposition, and to determine whether removal of SAP could facilitate amyloid breakdown. SAP is universally present in amyloid deposits, is highly resistant to proteolysis, and binding of SAP to amyloid fibrils has been demonstrated to protect them from degradation.1,2 Plasma levels of SAP are related to amyloidogenesis, and mice with targeted deletion of the SAP gene show retarded and reduced induction of amyloidosis. Based on this evidence, the authors decided to test whether removal of SAP from amyloid could lead to the breakdown of amyloid deposits.3
Initially, researchers identified a substance, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl] pyrrolidine-2-carboxylic acid (CPHPC), which inhibits SAP binding to amyloid fibres. CPHPC was found to cross-link pairs of pentameric human SAP molecules. The metabolism and excretion of CPHPC was determined and its function was tested in mouse models of amyloidosis. Continuous infusion of CPHPC over five days accelerated whole-body clearance of radiolabelled human SAP tracer, with which the amyloid deposits had previously been loaded, and removed all endogenous mouse SAP from the deposits. In addition, CPHPC provided in the drinking water to mice transgenic for a human SAP, led to significant reduction of amyloid in the treatment relative to a control group.
CPHPC was then administered for 48h by IV infusion to seven patients with systemic amyloidosis. Circulating SAP levels were rapidly and consistently depleted in all subjects. Direct evidence for depletion of SAP from amyloid was obtained by whole-body scintigraphy using 123I-labelled SAP as a tracer.
Finally, in an open-label study, CPHPC was infused intravenously into 19 patients with sytemic amyloidosis for a period of 1.2-9.5 months. Throughout treatment, plasma SAP values were reduced to 5% of pre-treatment levels in all patients, and there were no adverse clinical effects locally or systemically.
The binding of SAP stabilizes amyloid fibrils in vivo and protects them from proteolytic degradation. It is hoped that the removal of SAP will retard new amyloid deposition, reduce stability of current deposits and promote their regression. Currently, the authors are testing this hypothesis by long-term treatment of systemic amyloidosis in patients with CPHPC. It is hoped that CPHPC may be readily used not only for systemic amyloidosis, but also for diseases in which local amyloid deposits are implicated in pathogenesis.
Sources
- Pepys MB et al. Amyloid P component. A critical review. Int J Exp Clin Invest 1997; 4:274-95.
- Tennent GA, Lovat LB and Pepys MB. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer's disease and systemic amyloidosis. Proc Natl Acad Sci 1995; 92:4299-303.
- Pepys MB, Herbert J, Hutchinson WL et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 2002; 417: 254-9.
