Show simple item record

dc.contributor.authorOsborne, Andrew
dc.contributor.authorKhatib, Tasneem Z
dc.contributor.authorSongra, Lalana
dc.contributor.authorBarber, Amanda C
dc.contributor.authorHall, Katie
dc.contributor.authorKong, George YX
dc.contributor.authorWiddowson, Peter S
dc.contributor.authorMartin, Keith R
dc.date.accessioned2018-11-17T00:30:23Z
dc.date.available2018-11-17T00:30:23Z
dc.date.issued2018-09-26
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 improve 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 at least in part due 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.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAxons
dc.subjectRetinal Ganglion Cells
dc.subjectRetina
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectMice
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectDependovirus
dc.subjectOptic Nerve Injuries
dc.subjectGlaucoma
dc.subjectDisease Models, Animal
dc.subjectReceptor, trkB
dc.subjectBrain-Derived Neurotrophic Factor
dc.subjectMembrane Glycoproteins
dc.subjectSignal Transduction
dc.subjectDown-Regulation
dc.subjectIntraocular Pressure
dc.subjectMale
dc.subjectHEK293 Cells
dc.subjectGenetic Therapy
dc.subjectNeuroprotection
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.
dc.typeArticle
prism.issueIdentifier10
prism.publicationDate2018
prism.publicationNameCell Death Dis
prism.startingPage1007
prism.volume9
dc.identifier.doi10.17863/CAM.27349
dcterms.dateAccepted2018-09-07
rioxxterms.versionofrecord10.1038/s41419-018-1041-8
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09-26
dc.contributor.orcidHall, Katie [0000-0002-5612-5369]
dc.contributor.orcidMartin, Keith [0000-0002-9347-3661]
dc.identifier.eissn2041-4889
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCambridge Eye Trust (unknown)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
cam.issuedOnline2018-09-26


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

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