June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
QTA020V, a novel rAAV2 vector, delays retinal ganglion cell loss following optic nerve crush in the mouse
Author Affiliations & Notes
  • Keith R Martin
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    QUETHERA Ltd, Cambridge, United Kingdom
  • Andrew Osborne
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    QUETHERA Ltd, Cambridge, United Kingdom
  • Tasneem Khatib
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
  • Amanda Barber
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
  • George Kong
    Center for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia
    Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, Victoria, Australia
  • Peter S Widdowson
    QUETHERA Ltd, Cambridge, United Kingdom
  • Footnotes
    Commercial Relationships   Keith Martin, QUETHERA Ltd (I), QUETHERA Ltd (P), QUETHERA Ltd (C), QUETHERA Ltd (F); Andrew Osborne, QUETHERA Ltd (F); Tasneem Khatib, None; Amanda Barber, None; George Kong, None; Peter Widdowson, QUETHERA Ltd (E), QUETHERA Ltd (I), QUETHERA Ltd (P)
  • Footnotes
    Support  QUETHERA Ltd
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2954. doi:
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      Keith R Martin, Andrew Osborne, Tasneem Khatib, Amanda Barber, George Kong, Peter S Widdowson; QTA020V, a novel rAAV2 vector, delays retinal ganglion cell loss following optic nerve crush in the mouse. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2954.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : AAV-mediated BDNF expression has previously been shown to protect RGC in animal models of glaucoma, but long-term efficacy is compromised by TrkB receptor down-regulation. We designed a novel rAAV2 vector, QTA020V, capable of secreting mature BDNF (mBDNF) and enhancing TrkB receptor expression in RGCs. The efficacy of QTA020V in delaying RGC loss was assessed in a mouse model of optic nerve crush (ONC). Transgene expression and effects on visual function were also examined.

Methods : Adult mice were injected intravitreally with QTA020V (TrkB-viral-2A-mBDNF, CAG promoter), QTA024V (TrkB-viral-2A-mBDNF, human synapsin 1 promoter), QTA001V (proBDNF only, CAG promoter) or control (eGFP only, CAG promoter) (1-2μL, 1x1010 viral particles per eye). Unilateral ONC was performed 3 weeks later. Transgene expression and intraocular pressure (IOP) were assessed at multiple time points. Electroretinography (ERG) was used to measure the positive scotopic threshold response (pSTR), A-and B-wave in dark adapted mice. Surviving Brn3A-labelled RGCs were counted in retinal flat-mounts 7 days post-injury.

Results : Seven days after ONC, QTA020V transfected retinas, expressing mBDNF and TrkB, had 67% more surviving RGC than control eGFP injected eyes (1453±60 vs 868±34 cells/mm2; P<0.0001, n=7). RGC survival with QTA020V was greater than with a vector expressing BDNF alone (1135±53 cells/mm2; P<0.05 versus controls). Replacing the CAG promoter of QTA020V with the neuron-specific, but weaker, human synapsin 1 promoter reduced efficacy (surviving RGCs = 1223±89 cells/mm2; P<0.01 versus controls, n=9). Serial ERG recording did not show any significant changes between QTA020V-treated and either saline injected or untreated eyes. The pSTR component of the ERG, attributed to RGC, was not different in QTA020V, vehicle treated and naïve eyes (19.67±4.59 vs 17.81±2.69 vs 23.03±2.66μV, P=0.56, n=8). IOP was similar in all groups (QTA020V: 19.32±1.04mmHg; vehicle: 19.45±0.58 mmHg; naïve: 19.98±0.98 mmHg, n=5).

Conclusions : A novel, dual vector construct expressing TrkB and mBDNF under the regulation of the CAG promoter (QTA020V) had significantly greater efficacy in delaying RGC death than control and reference vectors expressing eGFP or proBDNF. Studies are ongoing to assess long term retinal transgene expression by QTA020V and its efficacy in reducing RGC death in experimental glaucoma.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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