کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6017795 | 1580166 | 2015 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Increased brain bio-distribution and chemical stability and decreased immunogenicity of an engineered variant of GDNF
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کلمات کلیدی
TGF-βUPDRSGap43DOPACGDNFNHPMPTPICVECMNGFGFRα1CEXkiloDaltonkDaDOPA6-OHDA1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine - 1-methyl-4-phenyl-1،2،3،6-tetrahydropyridine3,4-dihydroxyphenylalanine - 3،4-دی هیدروکسی فنیل آلانین6-hydroxy-dopamine - 6-هیدروکسی دپامینl-3,4-dihydroxyphenylalanine - L-3،4-دی هیدروکسی فنیل آلانینl-DOPA - L-DOPAMAPK - MAPKHuman leukocyte antigen - آنتی ژن لوسکسی انسانHLA - آنتیژن گلبول سفید انسانیHeparin binding - اتصال هپارینIHC - ایمونوهیستوشیمیImmunohistochemistry - ایمونوهیستوشیمیHIC - اینCho - برایParkinson's disease - بیماری پارکینسونTransforming Growth Factor Beta - تبدیل بتا فاکتور رشدChinese Hamster Ovary - تخمدان هامستر چینیtyrosine hydroxylase - تیروزین هیدروکسیلازc-Ret - ج-بازنشستهDopamine - دوپامینdihydroxyphenylacetic acid - دی هیدروکسی فنیل اسیدهای اسیدNeurite outgrowth - رشد عصبیgrowth associated protein 43 - رشد پروتئینی مرتبط با آن 43BBB - سد خونی مغزیnerve growth factor - فاکتور رشد عصبGlial cell line-derived neurotrophic factor - فاکتور نوروتروفی مشتق از سلول گلیاییExtracellular matrix - ماتریکس خارج سلولیblood–brain-barrier - مانع خون مغزیmajor histocompatibility complex - مجموعه سازگاری بافتی اصلیMHC - مجموعه سازگاری بافتی اصلیnon-human primate - نخستیسانان غیرانسانیhomovanillic acid - هومووانیلیک اسیدmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenPutamen - پوسته، پوتامنHVA - چهCation exchange chromatography - کروماتوگرافی تبادل کاتیونیhydrophobic interaction chromatography - کروماتوگرافی تعامل هیدروفوبیLiquid chromatography/mass spectrometry - کروماتوگرافی مایع / طیف سنج جرمیDopamine turnover - گردش مالی دوپامین
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
عصب شناسی
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چکیده انگلیسی
Several lines of evidence indicate that Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for dopaminergic neurons. Direct parenchymal administration of GDNF is robustly neuroprotective and neurorestorative in multiple neurotoxin-based animal models (rat and non-human primate (NHP)) of Parkinson's Disease (PD), suggesting its potential as a therapeutic agent. Although small, open-label clinical trials of intra-putamenal administration of bacteria-derived, full length, wild type GDNF (GDNFwt) were efficacious in improving standardized behavioral scores, a double-blinded, randomized controlled trial failed to do so. We hypothesize that the lack of clinical efficacy of GDNFwt in the larger randomized trial was due to poor bio-distribution in the putamen and/or poor chemical stability while in the delivery device for prolonged time periods at 37 °C. The development of neutralizing antibodies in some patients may also have been a contributing factor. GDNFv is an engineered form of GDNFwt, expressed and purified from mammalian cells, designed to overcome these limitations, including removal of the N-terminal heparin-binding domain to improve its diffusivity in brain parenchyma by reducing its binding to extracellular matrix (ECM), and key amino acid substitutions to improve chemical stability. Intra-striatal administration of a single injection of GDNFv in the rat produced significantly greater brain distribution than GDNFwt, consistent with reduced binding to ECM. Using liquid chromatography/mass spectrometry (LS/MS) methods GDNFv was shown to have improved chemical stability compared to GDNFwt when stored at 37 °C for 4 weeks. In addition, GDNFv resulted in lower predicted clinical immunogenicity compared to GDNFwt, as demonstrated by reduced CD4 + T cell proliferation and reduced IL-2-induced secretion in peripheral blood mononucleated cells collected from volunteers representing the world's major histocompatibility complex (MHC) haplotypes. GDNFv was demonstrated to be pharmacologically equivalent to GDNFwt in the key parameters in vitro of GFRα1 receptor binding, c-Ret phosphorylation, neurite outgrowth, and in vivo in its ability to increase dopamine turnover (DA). GDNFv protected dopamine nerve terminals and neurons in a 6-hydroxy-dopamine (6-OHDA) rat model. In summary, we empirically demonstrate the superior properties of GDNFv compared to GDNFwt through enhanced bio-distribution and chemical stability concurrently with decreased predicted clinical immunogenicity while maintaining pharmacological and neurotrophic activity. These data indicate that GDNFv is an improved version of GDNF suitable for clinical assessment as a targeted regenerative therapy for PD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental Neurology - Volume 267, May 2015, Pages 165-176
Journal: Experimental Neurology - Volume 267, May 2015, Pages 165-176
نویسندگان
Rosamund C. Smith, Linda M. O'Bryan, Pamela J. Mitchell, Donmienne Leung, Mahmoud Ghanem, Jonathan M. Wilson, Jeff C. Hanson, Sandra Sossick, Jane Cooper, Lihua Huang, Kalpana M. Merchant, Jirong Lu, Michael J. O'Neill,