胶质细胞源性神经营养因子干预视网膜色素变性给药方式的研究进展
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摘要
视网膜色素变性(retinitis pigmentosa,RP)的治疗目前仍处于探索阶段。胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是目前研究中重要的神经营养因子,但其传统给药方式生物利用度相对较低。近年来GDNF安全有效的给药方式成为研究热点,包括经病毒载体或非病毒载体的基因工程法释药技术、经聚合物释放系统释药技术、经细胞移植释药技术、小分子触发器诱导产生GDNF等。本文就GDNF干预RP的给药方式进行综述。
Treatment for retinitis pigmentosa(RP)is still in an exploratory period at present.Glial cell line-derived neurotrophic factor(GDNF)is an important neurotrophic factor,but the conventional ophthalmic delivery of GDNF results in a very low bioavailability,so the safe and effective delivery of GDNF has become the hotspot in recent years,including viral or non-viral mediated gene therapy,polymer-release systems,cell transplantation and small molecules to induce GDNF.This article gives a brief overview on related research progress of new ophthalmic delivery of GDNF intervention in RP.
Treatment for retinitis pigmentosa(RP)is still in an exploratory period at present.Glial cell line-derived neurotrophic factor(GDNF)is an important neurotrophic factor,but the conventional ophthalmic delivery of GDNF results in a very low bioavailability,so the safe and effective delivery of GDNF has become the hotspot in recent years,including viral or non-viral mediated gene therapy,polymer-release systems,cell transplantation and small molecules to induce GDNF.This article gives a brief overview on related research progress of new ophthalmic delivery of GDNF intervention in RP.
引文
[1] NA K H,KIM H J,KIM K H,HAN S,KIM P,HANN H J,et al.Prevalence,age at diagnosis,mortality,and cause of death in retinitis pigmentosa in Korea-a nationwide population-based study[J].Am J Ophthalmol,2017,176:157-165.
[2] DIAS M F,JOO K,KEMP J A,FIALHO S L,DA SILVA CUNHA A J R,WOO S J,et al.Molecular genetics and emerging therapies for retinitis pigmentosa:Basic research and clinical perspectives[J].Prog Retin Eye Res,2018,63:107-131.
[3] WANG Y,QIN Y,GUO T,TANG C,LIU L,GAO D.High concentration of glial cell line-derived neurotrophic factor protects primary astrocytes from apoptosis[J].Dev Neurosci,2018,40(2):134-144.
[4] QU Y,LIU Y M,MAO Y C,JIN Z,GAO M J,ZHENG Z B.Expressions of glial cell line-derived neurotrophic factor and its tyrosine kinase receptor RET in the terminal rectum of fetal rats with congenital anorectal malformations at different gestational ages[J].Chin J Appl Clin Pediatr,2016,31(23):1829-1833.曲颜,刘远梅,毛羽晨,金祝,高明娟,郑泽兵.胶质细胞源性神经营养因子及其酪氨酸激酶受体RET 在不同胎龄先天性肛门直肠畸形胎鼠直肠末端的表达[J].中华实用儿科临床杂志,2016,31(23):1829-1833.
[5] LIN Y,CAI J.Research progress of nerve protection of glial cell line-derived neurotrophic factor[J].Chin J Pract Nerv Dis,2017,20(20):106-109.林昱,蔡晶.胶质源性神经营养因子神经保护作用的研究进展[J].中国实用神经疾病杂志,2017,20(20):106-109.
[6] GARBAYO E,ANSORENA E,LANA H,CARMONA-ABELLáN M D,MARCILLA I,LANCIEGO J L,et al.Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys[J].Biomaterials,2016,110:11-23.
[7] IBá?EZ C F,ANDRESSOO J O.Biology of GDNF and its receptors-Relevance for disorders of the central nervous system[J].Neurobiol Dis,2017,97(Pt B):80-89.
[8] SAAVEDRA A,BALTAZAR G,DUARTE E P.Driving GDNF expression:the green and the red traffic lights[J].Prog Neurobiol,2008,86(3):186-215.
[9] ANDRéS-GUERRERO V,BRAVO-OSUNA I,PASTORIZA P,MOLINA-MARTINEZ I T,HERRERO-VANRELL R.Novel technologies for the delivery of ocular therapeutics in glaucoma[J].J Drug Deliv Sci Technol,2017,42:181-192.
[10] POLITI L E,ROTSTEIN N P,CARRI N G.Effect of GDNF on neuroblast proliferation and photoreceptor survival:additive protection with docosahexaenoic acid[J].Invest Ophthalmol Vis Sci,2001,42(12):3008-3015.
[11] DEL RíO P,IRMLER M,ARANGO-GONZáLEZ B,FAVOR J,BOBE C,BARTSCH U,et al.GDNF-induced osteopontin from Muller glial cells promotes photoreceptor survival in Pde6brd1 mouse model of retinal degeneration[J].Glia,2011,59(5):821-832.
[12] KUCHARSKA J,Del RíO P,ARANGO-GONZALEZ B,GORZA M,FEUCHTINGER A,HAUCK S M,et al.Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa[J].J Neurochem,2014,130:227-240.
[13] SCHWARTZ S G,SCOTT I U,FLYNN H W,STEWART M W.Drug delivery techniques for treating age-related macular degeneration[J].Expert Opin Drug Deliv,2014,11(1):61-68.
[14] WONG F S,WONG C C,CHAN B P,LO A C.Sustained delivery of bioactive GDNF from collagen and alginate-based cell-encapsulating gel promoted photoreceptor survival in an inherited retinal degeneration model[J].PLoS One,2016,11(7):e0159342.
[15] DALKARA D,GOUREAU O,MARAZOVA K,SAHEL J A.Let there be light:gene and cell therapy for blindness[J].Hum Gene Ther,2016,27(2):134-147.
[16] SANFTNER L H M,ABEL H,HAUSWIRTH W W,FLANNERY J G.Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa[J].Mol Ther,2001,4(6):622-629.
[17] BRINGMANN A,REICHENBACH A.Role of Müller cells in retinal degenerations[J].Front Biosci,2001,6:E72-92.
[18] DALKARA D,KOLSTAD K D,GUERIN K I,HOFFMANN N V,VISEL M,KLIMCZAK R R,et al.AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa[J].Mol Ther,2011,19(9):1602-1608.
[19] ISHIKAWA H,TAKANO M,MATSUMOTO N,SAWADA H,IDE C,MIMURA O,et al.Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode[J].Gene Ther,2005,12(4):289-298.
[20] TOUCHARD E,HEIDUSCHKA P,BERDUGO M,KOWALCZUK L,BIGEY P,CHAHORY S,et al.Non-viral gene therapy for GDNF production in RCS rat:the crucial role of the plasmid dose[J].Gene Ther,2012,19(9):886-898.
[21] JOHNSON L N,CASHMAN S M,READ S P,KUMAR-SINGH R.Cell penetrating peptide POD mediates delivery of recombinant proteins to retina,cornea and skin[J].Vision Res,2010,50(7):686-697.
[22] READ S P,CASHMAN S M,KUMAR-SINGH R.POD nanoparticles expressing GDNF provide structural and functional rescue of light-induced retinal degeneration in an adult mouse[J].Mol Ther,2010,18(11):1917-1926.
[23] BINDER C,CASHMAN S M,KUMAR-SINGH R.Extended duration of transgene expression from pegylated POD nanoparticles enables attenuation of photoreceptor degeneration[J].PLoS One,2013,8(11):e82295.
[24] WONG F S Y,TSANG K K,LO A C Y.Delivery of therapeutics to posterior eye segment:cell-encapsulating systems[J].Neural Regen Res,2017,12(4):576-577.
[25] WONG H L,WANG M X,CHEUNG P T,YAO K M,CHAN B P.A 3D collagen microsphere culture system for GDNF-secreting HEK293 cells with enhanced protein productivity[J].Biomaterials,2007,28(35):5369-5380.
[26] ANDRéS-GUERRERO V,ZONG M,RAMSAY E,ROJAS B,SARKHEL S,GALLEGO B,et al.Novel biodegradable polyesteramide microspheres for controlled drug delivery in ophthalmology[J].J Control Release,2015,211:105-117.
[27] MAKADIA H K,SIEGEL S J.Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier[J].Polymers (Basel),2011,3(3):1377-1397.
[28] ANDRIEU-SOLER C,AUBERT-POU?SSEL A,DOAT M,PICAUD S,HALHAL M,SIMONUTTI M,et al.Intravitreous injection of PLGA microspheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse[J].Mol Vis,2005,11:1002-1011.
[29] GARCíA-CABALLERO C,PRIETO-CALVO E,CHECA-CASALENGUA P,GARCíA-MARTíN E,POLO-LLORENS V,GARCíA-FEIJOO J,et al.Six month delivery of GDNF from PLGA/vitamin E biodegradable microspheres after intravitreal injection in rabbits[J].Eur J Pharm Sci,2017,103:19-26.
[30] GREGORY-EVANS K,CHANG F,HODGES M D,GREGORY-EVANS C Y.Ex vivo gene therapy using intravitreal injection of GDNF secreting mouse embryonic stem cells in a rat model of retinal degeneration[J].Mol Vis,2009,15:962-973.
[31] GAMM D M,WANG S,LU B,GIRMAN S,HOLMES T,BISCHOFF N,et al.Protection of visual functions by human neural progenitors in a rat model of retinal disease[J].PLoS One,2007,2(3):e338.
[32] HU Z L,LI N,WEI X,TANG L,WANG T H,CHEN X M.Neuroprotective effects of BDNF and GDNF in intravitreally transplanted mesen-chymal stem cells after optic nerve crush in mice[J].Int J Ophthalmol,2017,10(1):35-42.
[33] TZAMERET A,SHER I,BELKIN M,TREVES A J,MEIR A,NAGLER A et al.Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy[J].Exp Eye Res,2014,118(1):135-144.
[34] LEVY M J F,BOULLE F,STEINBUSCH H W,HOVE D L A V D,KENIS G,LANFUMEY L.Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression[J].Psychopharmacology,2018,235(8),2195-2220.
[35] MITTON K P,GUZMAN A E,DESHPANDE M,BYRD D,DELOOFF C,MKOYAN K,et al.Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice[J].Mol Vis,2014,20:1527-1544.
[36] BHALLA S,JOSHI D,BHULLAR S,KASUGA D,PARK Y,KAY C N.Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid[J].Br J Ophthalmol,2013,97(7):895-899.
[37] BARANOV P,LIN H,MCCABE K,GALE D,CAI S,LIEPPMAN B,et al.A novel neuroprotective small molecule for glial cell derived neurotrophic factor induction and photoreceptor rescue[J].J Ocul Pharmacol Ther,2017,33(5):412-422.
[2] DIAS M F,JOO K,KEMP J A,FIALHO S L,DA SILVA CUNHA A J R,WOO S J,et al.Molecular genetics and emerging therapies for retinitis pigmentosa:Basic research and clinical perspectives[J].Prog Retin Eye Res,2018,63:107-131.
[3] WANG Y,QIN Y,GUO T,TANG C,LIU L,GAO D.High concentration of glial cell line-derived neurotrophic factor protects primary astrocytes from apoptosis[J].Dev Neurosci,2018,40(2):134-144.
[4] QU Y,LIU Y M,MAO Y C,JIN Z,GAO M J,ZHENG Z B.Expressions of glial cell line-derived neurotrophic factor and its tyrosine kinase receptor RET in the terminal rectum of fetal rats with congenital anorectal malformations at different gestational ages[J].Chin J Appl Clin Pediatr,2016,31(23):1829-1833.曲颜,刘远梅,毛羽晨,金祝,高明娟,郑泽兵.胶质细胞源性神经营养因子及其酪氨酸激酶受体RET 在不同胎龄先天性肛门直肠畸形胎鼠直肠末端的表达[J].中华实用儿科临床杂志,2016,31(23):1829-1833.
[5] LIN Y,CAI J.Research progress of nerve protection of glial cell line-derived neurotrophic factor[J].Chin J Pract Nerv Dis,2017,20(20):106-109.林昱,蔡晶.胶质源性神经营养因子神经保护作用的研究进展[J].中国实用神经疾病杂志,2017,20(20):106-109.
[6] GARBAYO E,ANSORENA E,LANA H,CARMONA-ABELLáN M D,MARCILLA I,LANCIEGO J L,et al.Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys[J].Biomaterials,2016,110:11-23.
[7] IBá?EZ C F,ANDRESSOO J O.Biology of GDNF and its receptors-Relevance for disorders of the central nervous system[J].Neurobiol Dis,2017,97(Pt B):80-89.
[8] SAAVEDRA A,BALTAZAR G,DUARTE E P.Driving GDNF expression:the green and the red traffic lights[J].Prog Neurobiol,2008,86(3):186-215.
[9] ANDRéS-GUERRERO V,BRAVO-OSUNA I,PASTORIZA P,MOLINA-MARTINEZ I T,HERRERO-VANRELL R.Novel technologies for the delivery of ocular therapeutics in glaucoma[J].J Drug Deliv Sci Technol,2017,42:181-192.
[10] POLITI L E,ROTSTEIN N P,CARRI N G.Effect of GDNF on neuroblast proliferation and photoreceptor survival:additive protection with docosahexaenoic acid[J].Invest Ophthalmol Vis Sci,2001,42(12):3008-3015.
[11] DEL RíO P,IRMLER M,ARANGO-GONZáLEZ B,FAVOR J,BOBE C,BARTSCH U,et al.GDNF-induced osteopontin from Muller glial cells promotes photoreceptor survival in Pde6brd1 mouse model of retinal degeneration[J].Glia,2011,59(5):821-832.
[12] KUCHARSKA J,Del RíO P,ARANGO-GONZALEZ B,GORZA M,FEUCHTINGER A,HAUCK S M,et al.Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa[J].J Neurochem,2014,130:227-240.
[13] SCHWARTZ S G,SCOTT I U,FLYNN H W,STEWART M W.Drug delivery techniques for treating age-related macular degeneration[J].Expert Opin Drug Deliv,2014,11(1):61-68.
[14] WONG F S,WONG C C,CHAN B P,LO A C.Sustained delivery of bioactive GDNF from collagen and alginate-based cell-encapsulating gel promoted photoreceptor survival in an inherited retinal degeneration model[J].PLoS One,2016,11(7):e0159342.
[15] DALKARA D,GOUREAU O,MARAZOVA K,SAHEL J A.Let there be light:gene and cell therapy for blindness[J].Hum Gene Ther,2016,27(2):134-147.
[16] SANFTNER L H M,ABEL H,HAUSWIRTH W W,FLANNERY J G.Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa[J].Mol Ther,2001,4(6):622-629.
[17] BRINGMANN A,REICHENBACH A.Role of Müller cells in retinal degenerations[J].Front Biosci,2001,6:E72-92.
[18] DALKARA D,KOLSTAD K D,GUERIN K I,HOFFMANN N V,VISEL M,KLIMCZAK R R,et al.AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa[J].Mol Ther,2011,19(9):1602-1608.
[19] ISHIKAWA H,TAKANO M,MATSUMOTO N,SAWADA H,IDE C,MIMURA O,et al.Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode[J].Gene Ther,2005,12(4):289-298.
[20] TOUCHARD E,HEIDUSCHKA P,BERDUGO M,KOWALCZUK L,BIGEY P,CHAHORY S,et al.Non-viral gene therapy for GDNF production in RCS rat:the crucial role of the plasmid dose[J].Gene Ther,2012,19(9):886-898.
[21] JOHNSON L N,CASHMAN S M,READ S P,KUMAR-SINGH R.Cell penetrating peptide POD mediates delivery of recombinant proteins to retina,cornea and skin[J].Vision Res,2010,50(7):686-697.
[22] READ S P,CASHMAN S M,KUMAR-SINGH R.POD nanoparticles expressing GDNF provide structural and functional rescue of light-induced retinal degeneration in an adult mouse[J].Mol Ther,2010,18(11):1917-1926.
[23] BINDER C,CASHMAN S M,KUMAR-SINGH R.Extended duration of transgene expression from pegylated POD nanoparticles enables attenuation of photoreceptor degeneration[J].PLoS One,2013,8(11):e82295.
[24] WONG F S Y,TSANG K K,LO A C Y.Delivery of therapeutics to posterior eye segment:cell-encapsulating systems[J].Neural Regen Res,2017,12(4):576-577.
[25] WONG H L,WANG M X,CHEUNG P T,YAO K M,CHAN B P.A 3D collagen microsphere culture system for GDNF-secreting HEK293 cells with enhanced protein productivity[J].Biomaterials,2007,28(35):5369-5380.
[26] ANDRéS-GUERRERO V,ZONG M,RAMSAY E,ROJAS B,SARKHEL S,GALLEGO B,et al.Novel biodegradable polyesteramide microspheres for controlled drug delivery in ophthalmology[J].J Control Release,2015,211:105-117.
[27] MAKADIA H K,SIEGEL S J.Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier[J].Polymers (Basel),2011,3(3):1377-1397.
[28] ANDRIEU-SOLER C,AUBERT-POU?SSEL A,DOAT M,PICAUD S,HALHAL M,SIMONUTTI M,et al.Intravitreous injection of PLGA microspheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse[J].Mol Vis,2005,11:1002-1011.
[29] GARCíA-CABALLERO C,PRIETO-CALVO E,CHECA-CASALENGUA P,GARCíA-MARTíN E,POLO-LLORENS V,GARCíA-FEIJOO J,et al.Six month delivery of GDNF from PLGA/vitamin E biodegradable microspheres after intravitreal injection in rabbits[J].Eur J Pharm Sci,2017,103:19-26.
[30] GREGORY-EVANS K,CHANG F,HODGES M D,GREGORY-EVANS C Y.Ex vivo gene therapy using intravitreal injection of GDNF secreting mouse embryonic stem cells in a rat model of retinal degeneration[J].Mol Vis,2009,15:962-973.
[31] GAMM D M,WANG S,LU B,GIRMAN S,HOLMES T,BISCHOFF N,et al.Protection of visual functions by human neural progenitors in a rat model of retinal disease[J].PLoS One,2007,2(3):e338.
[32] HU Z L,LI N,WEI X,TANG L,WANG T H,CHEN X M.Neuroprotective effects of BDNF and GDNF in intravitreally transplanted mesen-chymal stem cells after optic nerve crush in mice[J].Int J Ophthalmol,2017,10(1):35-42.
[33] TZAMERET A,SHER I,BELKIN M,TREVES A J,MEIR A,NAGLER A et al.Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy[J].Exp Eye Res,2014,118(1):135-144.
[34] LEVY M J F,BOULLE F,STEINBUSCH H W,HOVE D L A V D,KENIS G,LANFUMEY L.Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression[J].Psychopharmacology,2018,235(8),2195-2220.
[35] MITTON K P,GUZMAN A E,DESHPANDE M,BYRD D,DELOOFF C,MKOYAN K,et al.Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice[J].Mol Vis,2014,20:1527-1544.
[36] BHALLA S,JOSHI D,BHULLAR S,KASUGA D,PARK Y,KAY C N.Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid[J].Br J Ophthalmol,2013,97(7):895-899.
[37] BARANOV P,LIN H,MCCABE K,GALE D,CAI S,LIEPPMAN B,et al.A novel neuroprotective small molecule for glial cell derived neurotrophic factor induction and photoreceptor rescue[J].J Ocul Pharmacol Ther,2017,33(5):412-422.