A new surrogate marker for CNS pathology in Niemann–Pick disease type C?

Abstract

Over the past 20 years there has been unprecedented progressin the development of treatments for lysosomal storage diseases(LSDs) [1]. Enzyme replacement therapy (ERT) continues to expandwith clinical programmes in Niemann–Pick type B, MPS IV andmetachromatic leucodystrophy. One small molecule drug (miglu-stat) is approved for type 1 Gaucher disease and other substratereduction therapy (SRT) and chaperone approaches are in the pipe-line [2]. Indeed, it is possible that in the future physicians treatingGaucher disease may be able to choose from three different en-zyme preparations, two inhibitors of glucosyl ceramide synthesisand a chaperone.However, these treatments are not all equally efficacious. Onemajor obstacle is that there is no means of delivering significantamounts of enzyme across the blood–brain barrier. This meansthat whilst ERT canbe highlyeffective against the visceralmanifes-tations of LSDs, patients in whom CNS involvement is the majorfeature do not benefit. For the majority of LSDs, which involve stor-age and pathology in the brain, ERT is not currently a realisticoption.Considerable research activity is therefore currently focused ondeveloping strategies to target brain disease in these disorders,either using small molecules, gene therapy or methods to deliverenzymes across the blood–brain barrier.One major obstacle in designingclinical trialsis the definitionofsuitable clinical endpoints. Regulatory authorities demand con-trolled trials, which demonstrate statistically significant changesin quantifiable variables. Pharmaceutical companies want trialsto be completed in months rather than years. Unfortunately, theseare rare, neurodegenerative diseases, which show variable andunpredictable progression over long periods. We do not knowwhich aspects of CNS pathology may be stabilised or improvedby treatment and it is very difficult to decide which clinical mani-festations should be measured or to know how long it may take tosee a significant change.The situation would be greatly improved if there were validatedsurrogate markers of brain disease that could be monitored as sec-ondaryclinical endpoints. These wouldpotentiallyprovidean earlyindicator of efficacy, prior to significant changes in clinicalsymptoms.The utility of surrogate markers in the storage disease field isbest exemplified by type 1 Gaucher disease [3]. This is a visceralstorage disorder with the Gaucher macrophage being the centralcell type in the pathogenic cascade [4]. These cells secrete a num-ber of factors that can be measured in peripheral blood and used assurrogate markers to estimate the total storage cell burden in un-treated patients and measure the degree of improvement followingthe initiation of ERT or SRT [5].However, currentlythere are no equivalent markersfor measur-ing storage in the brain. The Holy Grail in this field would be toidentify a non-invasive method that could be performed in mosthospitals where the parameter being measured was closely linkedto the primary pathological events occurring in the brain. It wouldneed to correlate with disease severity and be altered by diseasemodifying therapies.Miglustat, a small molecule inhibitor of glucosylceramide syn-thesis, does cross the blood–brain barrier and has shown benefitwhen used for SRT in a number of mouse models of CNS glyco-sphingolipid storage diseases [6], including Niemann–Pick type C