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    Neuroprotection 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

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    Author
    Osborne, A; Khatib, TZ; Songra, L; Barber, AC; Hall, K; Kong, GYX; Widdowson, PS; Martin, KR
    Date
    2018-09-26
    Source Title
    Cell Death and Disease
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Martin, Keith; Kong, Yu
    Affiliation
    Ophthalmology (Eye & Ear Hospital)
    Metadata
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    Document Type
    Journal Article
    Citations
    Osborne, A., Khatib, T. Z., Songra, L., Barber, A. C., Hall, K., Kong, G. Y. X., Widdowson, P. S. & Martin, K. R. (2018). Neuroprotection 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. CELL DEATH & DISEASE, 9 (10), https://doi.org/10.1038/s41419-018-1041-8.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253791
    DOI
    10.1038/s41419-018-1041-8
    Abstract
    Previous 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.

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