15 May 2002. The idea of shrinking amyloid plaques by drawing Ab out of the brain and into the circulation, where it can be destroyed, lately has gained some acceptance. Just recently, circulating antibodies were shown to soak up brain Ab in mouse models of Alzheimer's (see ARF news story). An alternative would be to use a small molecule drug that would disrupt amyloid by targeting one of its constituents, ideally one that can be easily manipulated. Enter SAP, or serum amyloid P component.
SAP is a proteolytically inert glycoprotein that binds to all known amyloid fibrils and is thought to protect them from degradation. If SAP could be taken out of the equation, the fibrils might be more easily removed by the body's own clearance mechanisms. In tomorrow's Nature, Mark Pepys, Royal Free and University College Medical School, London, together with colleagues elsewhere, report on the development of a small-molecule drug, which dimerizes SAP. This prevents SAP from binding to amyloid and in this way exposes the amyloid to proteases. The drug, CPHPC, was found by its ability to block SAP binding to immobilized Ab fibrils. The palindromic molecule, its two identical ends separated by an alkyl chain, can cross-link two SAP molecules.
Pepys et al showed by x-ray crystallography that five molecules of CPHPC act like the nuts on a car wheel, binding two donut-shaped pentamers of SAP together to form a decamer. The drug rapidly cleared human SAP from transgenic mice expressing it. Within five days, mouse SAP was completely eliminated from amyloid deposits induced in normal animals.
Results in humans were similar. Intravenous infusion of CPHPC rapidly cleared SAP from the serum, and in patients with systemic amyloidosis (of monoclonal immunoglobulin light chain) whole body imaging showed that SAP was depleted from amyloid in the organs. The human study was not designed to assess whether symptoms improved in the patients, but Pepys said that some of them were in the end-stages of disease and remained stable during the course of treatment.
Whether CPHPC can shrink amyloid deposits remains to be seen, Leslie Iversen of King's College, London, points out in an accompanying News and Views. It is encouraging, however, that the drug is rapidly cleared from the body and has little or no side-effects, most likely because it is not metabolized, said Pepys, who is about to start a small clinical trial of the drug for Alzheimer's disease.-Tom Fagan.
Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfal T, Alanine A, Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature. 16 May 2002;(417):254-259. Abstract
Iversen L. Small drugs lead the attack. Nature. 16 May 2002;(417):231-233. Abstract