Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5739151 | Progress in Neurobiology | 2017 | 58 Pages |
Abstract
Approximately 1 in 5000-8000 children are born annually with a lysosomal storage disease (LSD), which affects their cells' ability to break down naturally occurring substrates. Accumulation, or “storage,” of undegraded substrates leads to a wide variety of clinical symptoms, and early mortality. Currently, for LSDs with central nervous system (CNS) involvement, there is no available treatment. Four methods of treatment are being explored in clinical trials and preclinical settings: enzyme replacement therapy, ex vivo gene therapy, in vivo gene therapy, and nanoparticle-based therapy. In general, each therapeutic approach has been hindered by an inability to cross the blood-brain barrier (BBB) without invasive intracranial surgeries. Also, once the treatment has entered the brain, it is difficult to ensure therapeutic levels of enzyme distributed evenly throughout the entire parenchyma. Enzyme replacement therapy (ERT) is the current standard of care for lysosomal diseases without CNS involvement. However, with the recent advent of nanoparticle-based therapy, direct targeting of either gene therapy or ERT to the brain has become plausible. Ex vivo gene therapy, in vivo gene therapy, ERT and nanoparticle-based therapies are explained, while synthesizing and analyzing their potential as clinical treatments targeted to the CNS. While difficulties in treating the entire brain remain, preclinical studies demonstrate profound therapeutic benefit in animal models and generate hope for successful translation to humans.
Keywords
α-L-iduronidaseNPDARSBTPP1ICAM-1HSCTSLNMLDDNase IASMPLGAGUSBIDUAapoBNeuNICVintracerebroventricularAAVGAGGLDDeoxyribonuclease Iα-N-acetylglucosaminidaseSDSHexosaminidase ATNFIgGLINCLLSDFDAPBCAIGF IIHexAeGFPORMOSILArylsulfatase BARSAGloboid cell leukodystrophyAng-2β-glucuronidaseHuman leukocyte antigenHLAenzyme replacement therapyApoeApolipoprotein Bapolipoprotein Eacid sphingomyelinaseInsulin-like growth factor-IINiemann-Pick diseaseLysosomal storage diseasetripeptidyl peptidase 1IntravenousCNSinjected doseFood and Drug AdministrationBBBsodium dodecyl sulfateHuman hepatocellular carcinoma cellscentral nervous systemtumor necrosis factorMetachromatic leukodystrophyBlood-brain barrierCSFCerebrospinal fluidIntercellular adhesion molecule 1MucopolysaccharidosisSolid lipid nanoparticleMPsNAGLUERTHep G2adeno-associated viralenhanced green fluorescence proteinneuron-specific nuclear proteinPoly(d,l-lactide-co-glycolide)polyethylene glycolPEGPolystyreneHematopoietic stem cell transplantationGalactocerebrosidaseGalCImmunoglobulin gammaGlycosaminoglycans
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Authors
Jessica M. Kelly, Allison Bradbury, Douglas R. Martin, Mark E. Byrne,