title: Normalization and improvement of CNS deficits in mice with Hurler syndrome after long-term peripheral delivery of BBB-targeted iduronidase.
abstract: Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application.
authors.affiliation: Molecular and Cell Therapy Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Salim S
authors.initials: SS
authors.lastname: El-Amouri
authors.affiliation: Molecular and Cell Therapy Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Dai
authors.affiliation: Molecular and Cell Therapy Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jing-Fen
authors.initials: JF
authors.lastname: Han
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.affiliation: Molecular and Cell Therapy Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA. Electronic address: dao.pan@cchmc.org.
authors.forename: Dao
authors.initials: D
authors.lastname: Pan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007068:Iduronidase / Q000235:genetics* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D014018:Tissue Distribution
chemical_list: D001057:Apolipoproteins E; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D007068:Iduronidase
references.citation: Curr Pharm Biotechnol. 2011 Jun;12(6):884-96
references.pmid: 21235445
references.citation: Blood. 2007 Jun 15;109(12):5223-9
references.pmid: 17353345
references.citation: Blood. 2012 Feb 2;119(5):1107-16
references.pmid: 22096239
references.citation: Mol Ther. 2006 Oct;14(4):514-24
references.pmid: 16893684
references.citation: Neuron. 2010 Jan 14;65(1):94-106
references.pmid: 20152116
references.citation: Metab Brain Dis. 2012 Jun;27(2):121-9
references.pmid: 22527994
references.citation: Semin Hematol. 2010 Jan;47(1):59-69
references.pmid: 20109613
references.citation: Brain Res. 2008 Jan 10;1188:241-53
references.pmid: 18022143
references.citation: Mol Ther. 2012 Oct;20(10):1893-901
references.pmid: 22828503
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2680-5
references.pmid: 24550296
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2999-3004
references.pmid: 23382178
references.citation: Mol Ther. 2013 Oct;21(10):1938-49
references.pmid: 23748415
references.citation: Annu Rev Biochem. 2002;71:405-34
references.pmid: 12045102
references.citation: Exp Neurol. 2001 Apr;168(2):242-9
references.pmid: 11259112
references.citation: J Neurosci. 2003 Jun 15;23(12):5197-207
references.pmid: 12832544
references.citation: J Neurosci. 2014 Feb 26;34(9):3122-9
references.pmid: 24573272
references.citation: Drug Discov Today. 2007 Jan;12(1-2):54-61
references.pmid: 17198973
references.citation: Stem Cells. 2011 Oct;29(10):1479-84
references.pmid: 21898683
references.citation: Hum Gene Ther. 2012 Dec;23(12):1237-46
references.pmid: 22909060
references.citation: Orphanet J Rare Dis. 2011 Aug 10;6:55
references.pmid: 21831279
references.citation: J Clin Invest. 2008 Sep;118(9):3143-50
references.pmid: 18688286
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14944-9
references.pmid: 9843995
references.citation: Gene Ther. 2007 Jul;14(14):1065-77
references.pmid: 17460717
references.citation: Gene Ther. 2013 Apr;20(4):450-9
references.pmid: 23303281
references.citation: Science. 2013 Aug 23;341(6148):1233158
references.pmid: 23845948
references.citation: Blood. 2007 Apr 15;109(8):3270-8
references.pmid: 17170123
references.citation: N Engl J Med. 2004 May 6;350(19):1960-9
references.pmid: 15128896
references.citation: Gene Ther. 2006 Jun;13(11):917-25
references.pmid: 16482204
references.citation: J Gene Med. 2008 Mar;10(3):249-59
references.pmid: 18076130
references.citation: Blood. 2010 Dec 9;116(24):5130-9
references.pmid: 20847202
references.citation: Gene Ther. 2000 Nov;7(21):1875-83
references.pmid: 11110421
references.citation: Glycobiology. 2003 Sep;13(9):647-53
references.pmid: 12773478
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1902-7
references.pmid: 12576554
references.citation: Neurosci Biobehav Rev. 2014 May;42:193-207
references.pmid: 24594194
references.citation: J Atheroscler Thromb. 2004;11(4):200-8
references.pmid: 15356379
references.citation: EMBO Mol Med. 2013 Nov;5(11):1642-61
references.pmid: 24106209
references.citation: Curr Med Chem. 2010;17(12):1125-38
references.pmid: 20175745
references.citation: Mol Ther. 2000 Jan;1(1):63-70
references.pmid: 10933913
references.citation: Physiol Rev. 2008 Jul;88(3):887-918
references.pmid: 18626063
references.citation: Nat Rev Neurosci. 2012 Sep;13(9):619-35
references.pmid: 22895474
references.citation: Adv Anat Embryol Cell Biol. 1980;59:I-VI,1-62
references.pmid: 6996438
references.citation: Hum Mol Genet. 2010 Jun 1;19(11):2208-27
references.pmid: 20203170
references.citation: Mol Ther. 2012 Jul;20(7):1393-9
references.pmid: 22588273
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19958-63
references.pmid: 19903883
references.citation: Science. 2003 Oct 17;302(5644):415-9
references.pmid: 14564000