For personal use. Only reproduce with permission from The Lancet Publishing Group.

THE LANCET Neurology Vol 1 July 2002 http://neurology.thelancet.com142

Newsdesk

A new drug has the potential to removeamyloid by binding to serum amyloid Pcomponent (SAP), a protein that makesamyloid fibrils resistant to degradation.“The low molecular weight drugchanges the conformation of SAP sothat it is very rapidly cleared from thecirculation by the liver. If the drug canpromote regression of amyloid depositsin humans, it should be readilyapplicable not only in systemicamyloidosis, but also in Alzheimer’sdisease and type 2 diabetes,” comments

lead author Mark Pepys (Royal Freeand University Hospital MedicalSchool, London, UK).

Pepys and colleagues identified aspecific inhibitor of SAP using a high-throughput assay against immobilisedamyloid-� fibrils. The low molecularweight compound was then dimerisedto improve SAP-binding potency. Theresulting drug, CPHPC, blocks ligand-binding sites on individual SAPprotomers, preventing it from attachingto amyloid, and also crosslinks pairs of

SAP molecules, leading to their rapidclearance by the liver. Infusion ofCPHPC for 48 h in patients withsystemic amyloidosis caused rapid andconsistent depletion of circulating SAPin all seven patients. The patients withthe most severe amyloidosis stillshowed a plasma SAP concentrationbelow 25% of its original level 20 daysafter CPHPC infusion was stopped,suggesting, says Pepys, “that even abrief infusion of CPHPC hadsubstantially depeleted the amyloid-associated SAP pool in the tissues.”

Other results confirmed that thedrug had substantially removed SAPfrom amyloid. Finally, the groupcarried out a longer-term open-labelstudy in 19 patients, who were treatedwith 30–40 mg of CPHPC daily for 1 to10 months. Most patients remainedclinically stable during the treatment,despite all having end-stage disease thathad not responded to other therapy(Nature 2002; 417: 254–59).

“This study goes a long way toproving the concept that dissociatingSAP from amyloid deposits can makethem accessible to the body’s normalremoval mechanisms”, commentsLeslie Iversen (Wolfson Centre for AgeRelated Diseases, King’s College,London, UK) in an accompanyingeditorial (Nature 2002; 417: 232–33). Inthe current trial, the next phase will beto stop treatment after 6 or 12 months.“When plasma SAP returns to normal,indicating that SAP has fully re-equilibrated between the blood andamyloid pools, it will be possible to re-examine the patients using SAPscintigraphy to determine whetherprolonged CPHPC treatment hasactually promoted regression ofamyloid deposit”, explains Pepys.

A preliminary study of CPHPC in asmall number of patients withAlzheimer’s disease is also about tostart, in collaboration with MartinRossor (UCL Institute of Neurology,London, UK). “We will examine drugtolerability and its effects on SAP, A�,tau, and other markers in the CSF,whilst monitoring cognitive functionand brain changes using quantitativeMRI imaging”, reports Pepys.Kathryn Senior

Drug with potential to clear amyloid

US researchers have discovered apeptide that could help neurons toregenerate after CNS injury. It couldbe an “effective therapeutic agent inconditions characterised by failure of axonal regeneration”, such asspinal-cord injury, brain trauma,stroke, and multiple sclerosis, theinvestigators suggest.

“Previous work has shown that white matter of the braincontains a protein, called Nogo, thatis capable of limiting axon growththrough a Nogo receptor on axons”,says lead researcher StephenStrittmatter (Yale University, NewHaven, CT, USA). A 66 amino acid residue (Nogo-66) within the molecule is responsible forpreventing axonal regrowth. In thepresent study, Strittmatter andcolleagues tested the efficacy ofNogo receptor antagonists, derivedfrom fragments of Nogo-66, in ratswith mid-thoracic spinal cord hemisection. They found thatintrathecal administration of theantagonist NEP1 40 caused sig-nificant axonal sprouting andfunctional recovery (Nature 2002;417: 547–51).

“Therapeutically, this might havelarge implications”, says Strittmatter.“However, a number of stepsremain. Optimisation of the Nogoreceptor antagonist and assays for toxicity must still be performedin animals before it would be appropriate to consider a clinical trial.”

Karim Fouad (University ofAlberta, Canada) comments thatthese results are “very exciting”.However, he urged caution whenspeculating about the potentialtherapeutic effects of Nogoinhibition. “The role of Nogo in thehuman CNS is still unknown, andundesired side-effects of facilitatedaxonal sprouting and growth mightoccur.” Future studies usingknockout or transgenic animalmodels, as well as long-term studies,will be essential to resolve theseissues, he notes.

Fouad adds that Nogo is just oneof several obstacles preventingaxonal regeneration after spinal-cordinjury, and it is likely that acombination of therapies could beneeded to treat spinal-cord damageeffectively. These might includecellular grafts to bridge the lesionsite, such as Schwann cells, olfactoryensheathing cells, or stem cells;application of neurotrophic factorsto enhance axonal survival andgrowth; and degradation of chon-droitin sulphate proteoglycans withchondroitinase ABC (see The LancetNeurology 2002; 1: 78). “Combina-tions with bridging techniques willdefinitely be required for treatingsevere or even anatomically completespinal-cord injuries”, says Fouad,“since the neutralisation of Nogo byitself will not be sufficient to allowaxonal growth through scar tissueand the lesion site”.Helen Frankish

Peptide promotes axonal regrowth