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dc.contributor.authorOsborne, Andrewen
dc.contributor.authorKhatib, Tasneem Zen
dc.contributor.authorSongra, Lalanaen
dc.contributor.authorBarber, Amanda Cen
dc.contributor.authorHall, Katieen
dc.contributor.authorKong, George YXen
dc.contributor.authorWiddowson, Peter Sen
dc.contributor.authorMartin, Keithen
dc.date.accessioned2018-11-17T00:30:23Z
dc.date.available2018-11-17T00:30:23Z
dc.date.issued2018-09-26en
dc.identifier.issn2041-4889
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285329
dc.description.abstractPrevious studies have demonstrated that intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury. BDNF gene therapy can improved RGC survival in experimental models of glaucoma, the leading cause of irreversible blindness worldwide. However, the therapeutic efficacy of BDNF supplementation alone is time limited due at least in part to BDNF receptor downregulation. Tropomyosin-related receptor kinase-B (TrkB) downregulation has been reported in many neurological diseases including glaucoma, potentially limiting the effect of sustained or repeated BDNF delivery. Here we characterize a novel adeno-associated virus (AAV) gene therapy (AAV2 TrkB-2A-mBDNF) that not only increases BDNF production but also improves long term neuroprotective signaling by increasing expression of the BDNF receptor (TrkB) within the inner retina. This approach leads to significant and sustained elevation of survival signaling pathways ERK and AKT within RGCs over 6 months and avoids the receptor downregulation which we observe with treatment with AAV2 BDNF alone. We validate the neuroprotective efficacy of AAV2 TrkB-2A-mBDNF in a mouse model of optic nerve injury, where it outperforms conventional AAV2 BDNF or AAV2 TrkB therapy, before showing powerful proof of concept neuroprotection of RGCs and axons in a rat model of chronic intraocular pressure (IOP) elevation. We also show that there are no adverse effects of the vector on retinal structure or function as assessed by histology and electroretinography in young or aged animals. Further studies are underway to explore the potential of this vector as a candidate for progression into clinical studies to protect RGCs in patients with glaucoma and progressive visual loss despite conventional IOP-lowering treatment.
dc.description.sponsorshipThis work was supported by the Wellcome Trust (Pathfinder Award), the Midven Rainbow Seed Fund, Quethera Ltd, University of Cambridge Enterprise, the HB Allen Charitable Trust and the Cambridge Eye Trust.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAxonsen
dc.subjectRetinal Ganglion Cellsen
dc.subjectRetinaen
dc.subjectAnimalsen
dc.subjectMice, Inbred C57BLen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectRatsen
dc.subjectRats, Sprague-Dawleyen
dc.subjectDependovirusen
dc.subjectOptic Nerve Injuriesen
dc.subjectGlaucomaen
dc.subjectDisease Models, Animalen
dc.subjectReceptor, trkBen
dc.subjectBrain-Derived Neurotrophic Factoren
dc.subjectMembrane Glycoproteinsen
dc.subjectSignal Transductionen
dc.subjectDown-Regulationen
dc.subjectIntraocular Pressureen
dc.subjectMaleen
dc.subjectHEK293 Cellsen
dc.subjectGenetic Therapyen
dc.subjectNeuroprotectionen
dc.titleNeuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling.en
dc.typeArticle
prism.issueIdentifier10en
prism.publicationDate2018en
prism.publicationNameCell death & diseaseen
prism.startingPage1007
prism.volume9en
dc.identifier.doi10.17863/CAM.27349
dcterms.dateAccepted2018-09-07en
rioxxterms.versionofrecord10.1038/s41419-018-1041-8en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-09-26en
dc.contributor.orcidMartin, Keith [0000-0002-9347-3661]
dc.identifier.eissn2041-4889
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCambridge Eye Trust (unknown)
pubs.funder-project-idMRC (MC_PC_12009)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International