Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: An anatomical and behavioral analysis

You, Song; Hellström, Mats; Pollett, Margaret A.; LeVaillant, Chrisna J; Moses, Colette; Rigby, Paul; Penrose, Marissa A.; Rodger, Jennifer; Harvey, Alan R.

doi:10.1016/j.expneurol.2016.03.006

Cited by 15 publications

(8 citation statements)

References 59 publications

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“…Fold changes in the enriched GCL were greater than in whole retinal samples, and generally greater after AAV-CNTF exposure, strongly suggesting that cells were reacting against the persistent growth stimulus provided by the enhanced presence of transgenic neurotrophic proteins. With specific regard to retinal function, while we recently obtained evidence of recovery of some basic visual responses in AAV-CNTF injected rats with peripheral nerve bridges linking the transected optic nerve to visual midbrain, 22 long-term gene therapy induced changes such as those described here and elsewhere 25 almost certainly have an impact on retinal physiology. For example, others have shown that intraocular CNTF can adversely affect photoreceptor function, 18,19,40,41 the effect apparently being dose-dependent, 19,41 and CNTF induced upregulation of Socs3 , although not as great when using vectors compared with recombinant protein, 29,42 may also indirectly affect retinal vasculature.…”

Section: Discussionmentioning

confidence: 60%

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

LeVaillant

Sharma

Muhling

et al. 2016

Molecular Therapy - Methods & Clinical Development

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Use of viral vectors to deliver therapeutic genes to the central nervous system holds promise for the treatment of neurodegenerative diseases and neurotrauma. Adeno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells. However, these growth-inducing transgenes are driven by a constitutively active promoter, thus we examined whether long-term AAV-mediated secretion of BDNF or CNTF affected endogenous retinal gene expression. One year after the intravitreal injection of AAV-green fluorescent protein (GFP), bi-cistronic AAV-BDNF-GFP or AAV-CNTF-GFP, mRNA was extracted and analyzed using custom 96 well polymerase chain reaction arrays. Of 93 test genes, 56% showed significantly altered expression in AAV-BDNF-GFP and/or AAV-CNTF-GFP retinas compared with AAV-GFP controls. Of these genes, 73% showed differential expression in AAV-BDNF versus AAV-CNTF injected eyes. To focus on retinal ganglion cell changes, quantitative polymerase chain reaction was undertaken on mRNA (16 genes) obtained from fixed retinal sections in which the ganglion cell layer was enriched. The sign and extent of fold changes in ganglion cell layer gene expression differed markedly from whole retinal samples. Sustained and global alteration in endogenous mRNA expression after gene therapy should be factored into any interpretation of experimental/clinical outcomes, particularly when introducing factors into the central nervous system that require secretion to evoke functionality.

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Section: Discussionmentioning

confidence: 60%

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

LeVaillant

Sharma

Muhling

et al. 2016

Molecular Therapy - Methods & Clinical Development

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“…Perhaps investigators could perform similar complete transection to validate optic nerve regeneration, at least for the most promising strategies. In this regard, it is worth noting that studies that use complete optic nerve transection and peripheral nerve autograft showed long-distance regeneration of severed adult rat RGC axons resulting in extensive reinnervation of central visual targets (Thanos et al, 1997; You et al, 2016). Moreover, lens injury has been shown to promote RGC axon regeneration even after complete optic nerve transection in adult rats (Fischer et al, 2001).…”

Section: More Stringent Injuries?mentioning

confidence: 99%

Optic nerve regeneration in mammals: Regenerated or spared axons?

Fischer

Harvey

Pernet

et al. 2017

Experimental Neurology

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Intraorbital optic nerve crush in rodents is widely used as a model to study axon regeneration in the adult mammalian central nervous system. Recent studies using appropriate genetic manipulations have revealed remarkable abilities of mature retinal ganglion cell (RGC) axons to regenerate after optic nerve injury, with some studies demonstrating that axons can then go on to re-innervate a number of central visual targets with partial functional restoration. However, one confounding factor inherent to optic nerve crush injury is the potential incompleteness of the initial lesion, leaving spared axons that later on could erroneously be interpreted as regenerating distal to the injury site. Careful examination of axonal projection pattern and morphology may facilitate separating spared from regenerating RGC axons. Here we discuss morphological criteria and strategies that may be used to differentiate spared versus regenerated axons in the injured mammalian optic nerve.

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“…CNTF has been selected because it is known to promote the survival of injured CSN [ 6 ], and in other systems it promotes long-distance regeneration of injured adult CNS axons [ 7 – 10 ], with at least some functional outcomes [ 11 ]. CNTF is a neuropoietic member of the interleukin 6 (IL-6) cytokine family, expressed primarily in glial cells of the nervous system [ 12 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Functional improvement and enhanced remyelination has also been reported after intraspinal transplantation of oligodendrocyte precursor cells expressing CNTF [ 21 ]. However, as we have argued [ 2 ], while most SCI studies have targeted the injured cord itself for therapy, in other systems—such as the visual system—targeting the injured neurons themselves yields excellent functional outcomes [ 11 , 22 ]. Most importantly there is now clear evidence in human postmortem material that there is long-term survival of CSN after SCI [ 23 ], making strategies that target these neurons of genuine clinical relevance, potentially in both acute and chronic circumstances.…”

Section: Introductionmentioning

confidence: 99%

Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats

et al. 2018

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Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations.

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Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: An anatomical and behavioral analysis

Cited by 15 publications

References 59 publications

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

Optic nerve regeneration in mammals: Regenerated or spared axons?

Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats

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