The final frontier -- crossing the blood-brain barrier

The final frontier –crossing the

blood-brain barrier

William S.Sly 1*,Carole Vogler 2

Keywords:gene therapy;lysosomal storage diseases;mucopolysaccharidosis;sulfamidase;transcytosis See related article in EMBO Molecular Medicine http://www.77cn.com.cn/10.1002/emmm.201202083Despite the encouraging results with enzyme replacement therapy for several lysosomal storage diseases (LSDs),suc-cessful delivery of enzyme to brain to correct central nervous system (CNS)storage has been an elusive target (Grubb et al,2010).In that regard,the paper by Sorrentino et al (2013)in this issue is a major breakthrough.It is likely to gen-erate widespread interest and have a large impact on research in the ?eld.Why is this work so important?Most of the LSDs have some element of CNS involvement.In many of them,like San?lippo disease type IIIA,CNS invol-vement is the dominant feature (Rozaklis et al,2011).Correction of this aspect of LSDs that profoundly affects brain and leads to progressive neurological dete-rioration has posed the greatest chal-lenge.Successfully meeting that chal-

lenge is a big deal!Access of corrective enzyme to lyso-somes in cells of most tissues relies on receptor-mediated endocytosis,by the ubiquitously expressed mannose-6-phos-

phate (Man-6-P)receptor and mannose receptors on cells of the macrophage lineage.Cells in the CNS have limited access to enzymes targeting these recep-

tors.Indeed,the blood–brain barrier (BBB)effectively blocks access of such proteins except in the perinatal period.In the mouse,access to Man-6-P receptors on the brain capillaries is limited to the ?rst 2weeks of life,after which the brain becomes very resistant to infused native enzyme (Urayama et al,2008).For this reason,effective clearance of established CNS storage by infused enzymes has been quite limited.More invasive approaches involving direct injection of enzyme into the cerebrospinal ?uid intrathecally,or into the brain itself,have shown promise (Fraldi et al,2007).In fact,clinical trials are underway to evaluate intrathecal therapy.In urgent situations like spinal cord compression,such aggressive mea-sures are acceptable.However,more widespread application in humans may be impractical.Some success in delivering enzyme to brain with conventional enzyme therapy,but in higher than conventional doses,has been obtained in several animal models (Vogler et al,2005).In most cases,the correction was limited.These studies suggested that prolonged expo-sure to circulating enzyme,whether achieved by repeatedly infusing large doses,or by chemically modifying the enzyme to delay its clearance,enhanced the likelihood of neuronal correction.What appeared to be a signi?cant advance in extending the circulating lifetime of b -glucuronidase by chemical modi?cation

and enhancing CNS correction in the adult

mouse model of mucopolysaccharidosis (MPS)VII (Grubb et al,2010)proved not

to be useful in the murine models of MPS IIIA (Rozaklis et al,2011)and juvenile neuronal ceroid lipofuscinosis (Batten

disease)(Meng et al,2012).These diseases

and many others like them still need a

breakthrough.

Sorrentino et al (2013)improved on their own prior work and that of others using several clever strategies.They chose the well-characterized murine model

for MPS IIIA (San?lippo type IIIA).This

naturally occurring mouse model has progressive neurological disease due to de?ciency of sulphamidase (SGSH)which results in inability to degrade heparan sulphate in the CNS.The pathophysiology and predictable course had been very well de?ned by Rozaklis et al (2011),who showed that the CNS storage was resistant Closeup OPEN

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Crossing the blood-brain barrier »Why is this work so important?Most of the LSDs have some element of CNS involvement.In many of them,like Sanfilippo disease

type IIIA,CNS involvement is the dominant feature.Correction of this aspect of LSDs that profoundly affects brain and leads to progressive neurological deterioration has posed the greatest challenge.Successfully meeting that challenge is a big deal!«(1)Edward A.Doisy Department of Biochemistry and Molecular Biology,Saint Louis University School of Medicine,St.Louis,MO,USA (2)Department of Pathology,Saint Louis University

School of Medicine,St.Louis,MO,USA *Corresponding author:Tel:þ131********;Fax:þ131********;E-mail:slyws@slu.edu DOI 10.1002/emmm.201302668ß2013The Authors.Published by John Wiley and Sons,Ltd on behalf of EMBO.This is an open access article under

the terms of the Creative Commons Attribution License (CC BY 3.0),which permits use,distribution and reproduction

in any medium,provided the original work is properly cited.EMBO Mol Med (2013)5,655–657655

to even large doses of infused native or chemically modi?ed SGSH.

Sorrentino et al(2013)reasoned they might deliver enzyme by transcytosis, targeting a receptor that delivers an essential nutrient across the BBB.Trans-cytosis involves endocytosis at one cell surface(e.g.apical)followed rapidly by exocytosis at the opposite cell surface (e.g.basolateral)without delivery to lysosomes.Candidate receptors include the transferrin receptor,the insulin-like

growth factor receptor,and the LDL receptor(LDLR),each of which has been targeted in other work to deliver chimeric proteins to http://www.77cn.com.cnually an antibody to the relevant receptor was used as a ‘Trojan horse’to carry the desired protein across brain capillary endothelial cells (Zhou et al,2012).

Spencer and Verma(2007)had success-fully targeted the LDLR to deliver a virally expressed lysosomal enzyme to brain, providing proof of principle.Although correction of storage was not studied,they subsequently used this approach to deliver the protease neprilysin to brain in a transgenic Alzheimer mouse model.They showed not only ef?cacy in reducing brain accumulation of …… 此处隐藏：10220字，全部文档内容请下载后查看。喜欢就下载吧 ……