June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Neuroprotection of experimental anterior ischemic optic neuropathy using adenovirus-mediated enhancement of cAMP signaling in the perinuclear compartment
Author Affiliations & Notes
  • Ying Zhu
    Ophthalmology, Stanford University, Cupertino, California, United States
  • Louise Alessandra Mesentier-Louro
    Ophthalmology, Stanford University, Cupertino, California, United States
  • Xin Xia
    Ophthalmology, Stanford University, Cupertino, California, United States
  • Ali Shariati
    Ophthalmology, Stanford University, Cupertino, California, United States
  • Yaping Joyce Liao
    Ophthalmology, Stanford University, Cupertino, California, United States
  • Michael Kapiloff
    Ophthalmology, Stanford University, Cupertino, California, United States
  • Footnotes
    Commercial Relationships   Ying Zhu, None; Louise Mesentier-Louro, None; Xin Xia, None; Ali Shariati, None; Yaping Liao, None; Michael Kapiloff, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4585. doi:
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      Ying Zhu, Louise Alessandra Mesentier-Louro, Xin Xia, Ali Shariati, Yaping Joyce Liao, Michael Kapiloff; Neuroprotection of experimental anterior ischemic optic neuropathy using adenovirus-mediated enhancement of cAMP signaling in the perinuclear compartment. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4585.

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

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Abstract

Purpose : Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in those older than 50 years of age, and there is currently no effective therapy. Enhanced cyclic-AMP (cAMP) signaling is known to promote neuronal survival after injury, and this can occur in distinct compartments with high specificity to regulate different processes. We recently showed that enhanced perinuclear scaffold protein muscle A-kinase anchoring protein α (mAKAPα)-associated cAMP is sufficient to protect retinal ganglion cells (RGCs) in optic nerve crush model (Boczek, et al, J Neuroscience, 2019). In this study, we ask whether enhancement of mAKAPα-associated cAMP signaling in the perinuclear compartment using intravitreally injected adeno-associated virus construct can salvage RGCs in experimental AION.

Methods : We generated adeno-associated virus (AAV2) construct with enhanced perinuclear mAKAPα-associated cAMP signaling by expressing an anchoring disruptor peptide “4D3(E)” that only affects perinuclear cAMP-specific phosphodiesterase isoform PDE4D3 bound to mAKAPα (AAV2.4D3(E)-mCherry) or control (AAV2.mCherry). We performed intravitreal injection of the same AAV2 constructs bilaterally into adult C57BL6/J mice and induced photochemical thrombosis model of NAION in the right eye 2 weeks later. We measured optical coherence tomography (OCT) ganglion cell complex to track changes in retinal thickness before and 3 weeks after ischemia. Retinas were stained with RGC-specific marker (RBPMS) 4 weeks after ischemia. RGC survival was assessed by counting RBPMS-positive RGCs in 4 quadrants of the retina.

Results : Enhanced nuclear cAMP signaling via intravitreally injected AAV2 construct prior to NAION led to 33% preservation of the RGCs compared with eyes injected with control vector (p<0.01). There was no difference between treated NAION eyes compared with the contralateral control eye. There was no obvious OCT or histologic abnormality in control eyes injected with treatment or control constructs.

Conclusions : Enhanced perinuclear cAMP signaling at mAKAPα signalosomes promotes RGC survival after photochemical thrombosis model of NAION. Our study identifies a novel therapeutic approach that targets a highly specific neuronal compartment via cAMP-dependent signaling and confers neuroprotection in NAION and optic nerve crush.

This is a 2020 ARVO Annual Meeting abstract.

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