Type

Journal Article

Authors

Breandán Kennedy
Gerard Cagney
Walter Kolch
David J Duffy
Eugene T Dillon
J. J. O'Connor
Alison Reynolds
Sudhakar Deeti
Theresa Heffernan
Lisa Shine
and 1 others

Subjects

Medicine & Nursing

Topics
clinical trial hereditary eye disease neurodegneration treatment brain function histone deacetylase inhibitors blindness retinal degeneration brain derived neurotrophic factor cell death mechanisms of disease visual

A brain-derived neurotrophic factor mimetic is sufficient to restore cone photoreceptor visual function in an inherited blindness model (2017)

Abstract Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dyeucd6 model, we determined if treatment with HDACi can rescue cone photoreceptor-mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (~43 fold, p < 0.001) and visualmotor (VMR) (~3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue inour dataset. Cotreatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness.
Collections Ireland -> University College Dublin -> Biomolecular and Biomedical Science Research Collection
Ireland -> University College Dublin -> Conway Institute Research Collection
Ireland -> University College Dublin -> SBI Research Collection
Ireland -> University College Dublin -> Conway Institute
Ireland -> University College Dublin -> Medicine Research Collection

Full list of authors on original publication

Breandán Kennedy, Gerard Cagney, Walter Kolch, David J Duffy, Eugene T Dillon, J. J. O'Connor, Alison Reynolds, Sudhakar Deeti, Theresa Heffernan, Lisa Shine and 1 others

Experts in our system

1
Breandán N Kennedy
University College Dublin
Total Publications: 55
 
2
Gerard Cagney
Royal College of Surgeons in Ireland
Total Publications: 54
 
3
Walter Kolch
University College Dublin
Total Publications: 106
 
4
David J Duffy
University College Dublin
Total Publications: 17
 
5
Eugene T Dillon
University College Dublin
 
6
John J O'Connor
University College Dublin
Total Publications: 57
 
7
Alison Reynolds
University College Dublin
Total Publications: 20
 
8
Sudhakar Deeti
University College Dublin
 
9
Theresa Heffernan
University College Dublin
Total Publications: 3
 
10
Lisa Shine
University College Dublin