Transplantation of Schwann Cell Line Clones Secreting GDNF or BDNF into the Retinas of Dystrophic Royal College of Surgeons Rats

Lawrence, Jean M.; Keegan, David; Muir, Elizabeth M.; Coffey, Peter; Rogers, J. H.; Wilby, Martin; Fawcett, James W.; Lund, R.D.

doi:10.1167/iovs.03-0093

Cited by 110 publications

(74 citation statements)

References 22 publications

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“…Treatment with BDNF alone (without a graft) had no effect on the response latency which suggests that BDNF acts synergistically with other 'factors' released by the transplanted tissue. This combined effect may result in some restoration of the disturbed neural circuitry of the degenerating host retina which is supported by data from other investigators demonstrating neuro-protective effects of BDNF (Chaum, 2003;Ikeda et al, 2003;Keegan et al, 2003;Lawrence et al, 2004;Nakazawa et al, 2002;Paskowitz et al, 2004).…”

Section: Discussionmentioning

confidence: 54%

“…Studies performed in normal and retinal degenerate rat models demonstrate that BDNF has a neuroprotective role (Chaum, 2003;Gauthier et al, 2005;Ikeda et al, 2003;Keegan et al, 2003;Lawrence et al, 2004;Nakazawa et al, 2002;Paskowitz et al, 2004). Therefore, the present investigation evaluates the possible role of BDNF in promoting the functional efficacy of the retinal neuroblastic sheets transplanted into the subretinal space of retinal degenerative rats.…”

Section: Introductionmentioning

confidence: 99%

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BDNF-treated retinal progenitor sheets transplanted to degenerate rats: Improved restoration of visual function

Seiler

Thomas

Chen

et al. 2008

Experimental Eye Research

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The aim of this study was to evaluate the functional efficacy of retinal progenitor cell (RPC) containing sheets with BDNF microspheres following subretinal transplantation in a rat model of retinal degeneration. Sheets of E19 RPCs derived from human placental alkaline phosphatase (hPAP) expressing transgenic rats were coated with poly-lactide-co-glycolide (PLGA) microspheres containing brain-derived neurotrophic factor (BDNF) and transplanted into the subretinal space of S334ter line 3 rhodopsin retinal degenerate rats. Controls received transplants without BDNF or BDNF microspheres alone. Visual function was monitored using optokinetic head-tracking behavior. Visually evoked responses to varying light intensities were recorded from the superior colliculus (SC) by electrophysiology at 60 days after surgery. Frozen sections were studied by immunohistochemistry for photoreceptor and synaptic markers. Visual head tracking was significantly improved in rats that received BDNF-coated RPC sheets. Relatively more BDNF-treated transplanted rats (80%) compared to non-BDNF transplants (57%) responded to a ''low light'' intensity of 1 cd/m 2 in a confined SC area. With bright light, the onset latency of SC responses was restored to a nearly normal level in BDNF-treated transplants. No significant improvement was observed in the BDNF-only and no surgery transgenic control rats. The bipolar synaptic markers mGluR6 and PSD-95 showed normal distribution in transplants and abnormal distribution of the host retina, both with or without BDNF treatment. Red-green cones were significantly reduced in the host retina overlying the transplant in the BDNF-treated group. In summary, BDNF coating improved the functional efficacy of RPC grafts. The mechanism of the BDNF effectsdeither promoting functional integration between the transplant and the host retina and/or synergistic action with other putative humoral factors released by the RPCsdstill needs to be elucidated. Ó 2007 Elsevier Ltd. All rights reserved.Keywords: retinal transplantation; superior colliculus; head-tracking behavior; BDNF microsphere; retinal progenitor cells; S334terAbbreviations: BDNF, brain-derived neurotrophic factor; DAPI, 4 0 6 0 -diamidino-2-phenylindole hydrochloride; CNS, central nervous system; GC, ganglion cell layer; H, host retina; hPAP, human placental alkaline phosphatase; IN, inner nuclear layer; IP, inner plexiform layer; mGluR6, metabotropic glutamate receptor 6 (synaptic receptor on bipolar cells); ms, milliseconds; ON, outer nuclear layer; OP, outer plexiform layer; OS, outer segments; PBS, phosphate-buffered saline; PKC, protein kinase C (marker for rod bipolar cells); PLGA, poly-lactide-co-glycolide; PSD-95, post-synaptic density protein 95 (post-synaptic marker on bipolar cell dendrites); RG-opsin, red-green opsin; RPC, retinal progenitor cells; SC, superior colliculus; RCS, Royal College of Surgeons; RPE, retinal pigment epithelium; T, transplant.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

BDNF-treated retinal progenitor sheets transplanted to degenerate rats: Improved restoration of visual function

Seiler

Thomas

Chen

et al. 2008

Experimental Eye Research

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“…Within the implicated region of chromosome 5, we identified no obvious candidate genes for retinopathy, although several (GDNF, MCDR3, and SLC1A3) occur somewhat distal to this region (32)(33)(34). On chromosome 6, candidates in the implicated region include EDN1 and GMNN.…”

Section: Olr1mentioning

confidence: 84%

A Genome-Wide Linkage Scan for Diabetic Retinopathy Susceptibility Genes in Mexican Americans With Type 2 Diabetes From Starr County, Texas

et al. 2007

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We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions. Diabetes 56: 1167-1173, 2007 D iabetic retinopathy, a frequent complication of both type 1 and type 2 diabetes, is the fifth most common cause of legal blindness in the U.S. (1). Some degree of retinopathy occurs in virtually all type 1 and 60% of type 2 diabetic patients affected Ն20 years, although severe proliferative retinopathy is more frequent in type 1 diabetes. The underlying causes of diabetic retinopathy have not yet been elucidated, although tight control of hyperglycemia can retard its development and progression (1-4).Although studies of familial aggregation of diabetic retinopathy suggest that genes may influence either its onset (5,6) or its severity (7,8), most studies of the genetics of diabetic retinopathy have involved candidate genes. Polymorphisms in several genes have been associated with diabetic retinopathy, though few associations have been replicated in multiple populations (9). Exceptions include aldose reductase (10 -17) and the insertion/deletion polymorphism of the angiotensin I-converting enzyme (18,19), although the latter association has been questioned (20).In Pima Indians, a genomic scan revealed evidence of linkage between regions on chromosomes 3 and 9 and the occurrence of retinopathy in 136 affected siblings (103 affected pairs) with type 2 diabetes, with a maximum multipoint logarithm of odds (LOD) score of 1.46 for the region on chromosome 9 (21). We here report the results of a genome-wide linkage scan for the occurrence and severity of retinopathy in Mexican-American families from Starr County, Texas, having at least two siblings affected with type 2 diabetes. RESEARCH DESIGN AND METHODSMexican-American families from Starr County, Texas, having two or mor...

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“…GDNF was administered into the subretinal space in the rd1 mouse, 8,45 by transplantation of cells genetically engineered to secrete GDNF in the RCS rat 38,39 as well as by injection of recombinant adenoassociated virus --GDNF viral vectors in TgN S334ter-4 and RCS rats. 11,40 Only two studies have demonstrated that GDNF could exert similar effects when delivered in the vitreous, one in the rd1/rd1 mouse using microspheres 27 and the other one in the TgN S334ter-4 rat using transduced stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…Neurotrophic factors including GDNF 37 have short half-lives within the eye and injections should be repeated to achieve any efficacy. 8,26 Various strategies using microspheres, 27 cell transplantation 28,38,39 or viral gene therapy 11,40 have been attempted to release GDNF. However, no attempt has been made to date to deliver GDNF via a non-viral gene transfer method in any inherited model of RP.…”

Section: Introductionmentioning

confidence: 99%

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose

et al. 2011

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Glial cell line-derived neurotrophic factor (GDNF) is one of the candidate molecules among neurotrophic factors proposed for a potential treatment of retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous GDNF levels dropped during retinal degeneration time course, opening a therapeutic window for GDNF supplementation. We showed that after a single electrotransfer of 30 mg of GDNF-encoding plasmid in the rat ciliary muscle, GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of GDNF delayed photoreceptors (PRs) as well as retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of GDNF delivery through non-viral gene therapy in RP; (ii) establishing the efficacy of intravitreal administration of GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of GDNF within the eye/retina.

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Transplantation of Schwann Cell Line Clones Secreting GDNF or BDNF into the Retinas of Dystrophic Royal College of Surgeons Rats

Cited by 110 publications

References 22 publications

BDNF-treated retinal progenitor sheets transplanted to degenerate rats: Improved restoration of visual function

BDNF-treated retinal progenitor sheets transplanted to degenerate rats: Improved restoration of visual function

A Genome-Wide Linkage Scan for Diabetic Retinopathy Susceptibility Genes in Mexican Americans With Type 2 Diabetes From Starr County, Texas

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose

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