title: CNTF gene transfer protects ganglion cells in rat retinae undergoing focal injury and branch vessel occlusion.
abstract: Ciliary neurotrophic factor (CNTF) has been shown to protect ganglion cells in a variety of acute ischaemia models. Here we assess the efficacy of local CNTF gene transfer in protecting retinal ganglion cells when there is focal ischaemia combined with interruption of axoplasmic flow. This dual injury may be more representative of the pathological mechanisms operating in acute retinal diseases, such as vascular events acting at the optic nerve head. Fourteen rats received an intravitreal injection of an adeno-associated viral (AAV) vector expressing a secretable form of CNTF into the right eye and a control vector into the left eye. Three weeks later, each rat underwent a symmetrical small vertical 2mm standardised retinal crush injury approximately 2mm temporal to the optic disc. The injury also occluded the temporal retinal arteriole so that the axon crush was combined with an acute retinal infarction visible on fundoscopy. Changes in the damaged sector were compared histologically four weeks after injury and ganglion cell survival was estimated by comparing cell counts on retinal flat-mounts immunostained with RT-97 antibody. This mode of injury led to a profound loss of both the inner nuclear and ganglion cell layers, but was limited to the lesioned sector. In AAV.CNTF-treated eyes approximately 12% of ganglion cells survived compared with approximately 2% in control eyes (p=0.01). The scotopic electroretinogram (ERG), however, was reduced to about 50% in AAV.CNTF-treated eyes, both before and after injury. We therefore show that CNTF gene transfer confers neuroprotection to ganglion cells undergoing an acute ischaemic injury combined with interruption of axoplasmic flow. This approach may be relevant to optic nerve trauma and a variety of retinal vascular diseases that lead to swelling of the optic nerve head, provided CNTF can be delivered in a way that does not significantly suppress retinal function.
authors.affiliation: Division of Molecular Therapy, Institute of Ophthalmology, University College London, London EC1V 9EL, UK. mol.therapy@ucl.ac.uk
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
authors.forename: Prateek K
authors.initials: PK
authors.lastname: Buch
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Kamaljit S
authors.initials: KS
authors.lastname: Balaggan
authors.forename: Angus
authors.initials: A
authors.lastname: MacNeil
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Taylor
authors.forename: Neville N
authors.initials: NN
authors.lastname: Osborne
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001160:Arterioles; D001370:Axonal Transport / Q000502:physiology; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D020934:Ciliary Neurotrophic Factor / Q000235:genetics*; D004195:Disease Models, Animal; D004596:Electroretinography / Q000379:methods; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry / Q000379:methods; D007238:Infarction; D008297:Male; D018917:Optic Neuropathy, Ischemic / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D012160:Retina / Q000293:injuries* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology*
chemical_list: D020934:Ciliary Neurotrophic Factor