June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Restoration of vision using selective histone deacetylase 6 inhibitor, Tubastatin A, in models of inherited blindness
Author Affiliations & Notes
  • Breandan N Kennedy
    Sch of Biomolecular and Biomedical Sci, University College Dublin , Dublin, Ireland
  • Sarah Roche
    Biochemistry, University College Cork , Cork, Ireland
  • Matthew Brooks
    National Eye Institute, Bethesda, Maryland, United States
  • Eugene Dillon
    Sch of Biomolecular and Biomedical Sci, University College Dublin , Dublin, Ireland
  • Milton English
    National Eye Institute, Bethesda, Maryland, United States
  • Ailis Laura Moran
    Sch of Biomolecular and Biomedical Sci, University College Dublin , Dublin, Ireland
  • Anand Swaroop
    National Eye Institute, Bethesda, Maryland, United States
  • Husvinee Sundaramurthi
    Sch of Biomolecular and Biomedical Sci, University College Dublin , Dublin, Ireland
  • Footnotes
    Commercial Relationships   Breandan Kennedy, None; Sarah Roche, None; Matthew Brooks, None; Eugene Dillon, None; Milton English, None; Ailis Moran, None; Anand Swaroop, None; Husvinee Sundaramurthi, None
  • Footnotes
    Support  HRB/MRCG Research Project Grant. MSCA H2020 Topmed10
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2470. doi:
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      Breandan N Kennedy, Sarah Roche, Matthew Brooks, Eugene Dillon, Milton English, Ailis Laura Moran, Anand Swaroop, Husvinee Sundaramurthi; Restoration of vision using selective histone deacetylase 6 inhibitor, Tubastatin A, in models of inherited blindness. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2470.

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

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Abstract

Purpose : Inherited retinal dystrophies (IRD) affect 1 in 3000 people worldwide. Unfortunately, there is no suitable drug therapies. Several studies revealed neuroprotective effects of histone deacetylase inhibitors (HDACi). We investigated if selective HDAC6 inhibitors (HDAC6i) can rescue vision in zebrafish models of IRD and underlying mechanism of neuroprotection.

Methods : dying on edge (dye), a zebrafish IRD model, was treated with 100 µM Tubastatin A (TubA) for 3 days from 3 days post fertilization (dpf; n = 12, N = 3). At 6 dpf, visual capacity was measured by optokinetic response assays (OKR). A total of 60 larval eyes were collected per treatment group at 6 dpf and processed for transcriptomics (RNA sequencing, N = 5) and proteomics (Mass spectrometry, N = 3) analysis according to previously published studies. Retinal explants were obtained from rd10 mice at postnatal day 14 (P14) and treated with increasing concentrations (10 µM, 25 µM, 50 µM and 100 µM) of TubA, for four days. Treatment solution was changed every two days. Retinal morphology was analyzed by immunofluorescence assay. Statistical analysis was performed using one-way ANOVA with Dunnett’s multiple comparisons and two-tailed Student’s T-test.

Results : TubA treatment significantly restored vision in dye-/- from 0.7 saccades/minute on average to 7.9 saccades/minute (p < 0.0001). A total of 171 gene transcripts and 347 proteins were identified to be differentially expressed upon TubA treatment. The top-altered pathways from proteomics study included phototransduction, proteasome, endocytosis and amino acid metabolism. Interestingly, transcriptomics study indicated that inflammatory responses were strongly downregulated by TubA, while phototransduction and cellular transport specific genes were upregulated. TubA treatment resulted in a dose-dependent increase in the number of cone-arrestin positive cells in the outer nuclear layer with a significant increase from 6 to 12 cells (p = 0.0452) per field of view (FOV) in rd10 mice explants. Number of rhodopsin positive cells was not significantly altered.

Conclusions : Selective HDAC6i elicits with neuroprotection in the retina of different genetic models of IRD, acting as a potential therapeutic option. TubA mediates with neuroprotection by increasing proteins involved in proteasomal, endocytosis and phototransduction, while reducing inflammation

This is a 2020 ARVO Annual Meeting abstract.

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