Will Zapping SAP Knock Out AD?
July 1, 2002
Abstract & Commentary
Source: Pepys MB, et al. Nature. 2002;417:254-259.
Systemic and neurologic amyloidoses share in common the development of extracellular deposits composed of abnormally folded proteins within diseased tissues. Alzheimer’s disease (AD) is an example of an amyloidosis of the brain in which the abnormal protein is beta-amyloid. Several techniques are now under development to disrupt amyloid deposition as a possible means of averting these disorders. Pepys and colleagues have developed a new approach to amyloid treatment that increases systemic amyloid clearance in both preclinical studies and initial human trials. Their approach uses a newly identified small molecule that disrupts amyloid formation through the depletion of soluble amyloid protein (SAP) from the blood.
SAP is ubiquitous in amyloid deposits where it appears to play a role in stabilizing amyloid fibrils by protecting them from degradation. In a previous study of genetically manipulated mice lacking the SAP gene, the development of systemic amyloidosis AA was delayed and reduced in severity (Botto M, et al. Nature Medicine. 1997;3:885-889). This supported the hypothesis that depletion of SAP from the blood can permit physiologic mechanisms of amyloid clearance to become more effective.
Pepys et al screened for small molecules that inhibited binding of SAP to beta amyloid fibrils, the type found in plaques in AD. Among several possible candidates, a molecule designated as CPHPC was found to be optimal for clinical testing. CPHPC exhibited no adverse effects in toxicologic studies in rodents even at high concentrations, and was largely excreted without being further metabolized.
CPHPC was administered intravenously over a 48-hour period to 7 patients with systemic amyloidosis in an open-label clinical trial. In all cases, there was rapid depletion of SAP from the circulation, and reduction of SAP in blood continued for at least 20 days after the infusion was discontinued. Whole body scintigraphy provided evidence of SAP depletion from amyloid deposits throughout the body. Radiolabeled SAP localized heavily to the liver after the infusions, indicating that CPHPC-SAP complexes were being cleared hepatically. In further trials, a total of 19 patients with systemic amyloidosis received CPHPC either intravenously or subcutaneously. There were no adverse effects, and significant reductions in SAP levels were documented.
Pepys et al conclude that their studies provide proof of principle that small molecules can be used to selectively deplete a particular serum protein such as SAP for therapeutic ends. They express hope that removal of SAP from circulation will prove effective in destabilizing amyloid deposition throughout the body, therefore proving effective in treating a variety of human amyloidoses, including AD.
Commentary
There is substantial evidence that abnormal protein folding plays a role in the pathogenesis of a number of neurodegenerative disorders. In AD, deposition of beta amyloid is one of the earliest documented pathological events, and thereby an important target for prevention and treatment. Techniques for altering the production, fibrillogenesis, and clearance of beta amyloid from brain, are currently under investigation. Clear evidence from animal studies indicates that some amyloid deposits are mutable, and can be induced to regress by a variety of approaches. Recently, Elan performed human trials of a putative immunotherapeutic agent for AD (AN-1792) that involved generation of antibodies against beta-amyloid. Unfortunately, this had to be halted when several participants developed brain swelling. The Elan trial remains open for follow-up and may still yield information about the therapeutic efficacy of this approach. Another approach currently in human trials involves newly developed secretase inhibitors that inhibit production of pathogenic forms of the amyloid peptide. These trials have yet to progress beyond dose-finding stages, and are likely to require several years to reach completion. The zinc and copper chelating properties of the antibiotic Clioquinol have recently been shown to reduce amyloid deposition in transgenic mouse models of AD. This agent has shown some promise in a preliminary human trial. Several other agents with the potential of altering amyloid metabolism and clearance are being explored. Existing approaches may now be supplemented by the interesting small molecule approach pioneered by Pepys et al for SAP depletion.
The prospects for reversal of AD by systemic administration of a small molecule that depletes SAP seems somewhat remote for several reasons. It has not been established whether SAP is essential to the stabilization of neuritic plaques in AD brains, which are decorated with a variety of other proteins in addition to SAP. Even if depletion of SAP from the blood ultimately reduces extracellular amyloid burden in the brain, it is still not clear whether this will be effective in arresting or retarding the development of AD. The critical studies in humans have yet to be completed to test the amyloid cascade hypothesis of AD causation. The small molecule approach reported by Pepys et al appears to have extremely low toxicity, an important feature for putative therapies in the elderly population at risk for AD. It seems likely that variations on this theme will be tested in AD as well as disorders such as CJD, in which amyloid deposits are a recognized and arguably critical element of the neuropathology. —Norman R. Relkin
Dr. Relkin, Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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