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Targeting the HDAC6-Cilium Axis Ameliorates the Pathological Changes Associated with Retinopathy of Prematurity
Insights
Targeting HDAC6 may prevent retinopathy of prematurity (ROP), a leading cause of childhood blindness. Blocking HDAC6-mediated photoreceptor cilia disassembly protected mice from ROP-associated retinal defects.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Retinopathy of prematurity (ROP) is a major cause of pediatric visual impairment.
- Effective pharmacological treatments for ROP remain limited.
- HDAC6-mediated disassembly of photoreceptor cilia is a potential early factor in ROP development.
Purpose of the Study:
- To investigate the role of Histone deacetylase 6 (HDAC6) in the pathogenesis of ROP.
- To explore the potential of targeting the HDAC6-cilium axis for ROP prevention.
Main Methods:
- Adenovirus-mediated enhanced expression of HDAC6 in mice to induce ROP-like changes.
- Analysis of Hdac6 transgenic and knockout mice under oxygen-induced conditions.
- Assessment of retinal structure and function using electroretinography.
- Evaluation of small-molecule compounds targeting HDAC6 for protective effects.
Main Results:
- Enhanced HDAC6 expression induced ROP-typical retinal pathology and photoreceptor cilia disassembly in mice.
- Hdac6 transgenic mice displayed ROP-related defects, while Hdac6 knockout mice were protected from oxygen-induced retinal damage.
- Pharmacological inhibition of HDAC6-mediated cilium disassembly successfully protected mice against ROP-associated retinal defects.
Conclusions:
- HDAC6 plays a critical role in the pathogenesis of ROP by mediating photoreceptor cilia disassembly.
- Targeting the HDAC6-cilium pathway presents a promising therapeutic strategy for preventing ROP.
Abstract:
Retinopathy of prematurity (ROP) is one of the leading causes of childhood visual impairment and blindness. However, there are still very few effective pharmacological interventions for ROP. Histone deacetylase 6 (HDAC6)-mediated disassembly of photoreceptor cilia has recently been implicated as an early event in the pathogenesis of ROP. Herein it is shown that enhanced expression of HDAC6 by intravitreal injection of adenoviruses encoding HDAC6 induces the typical pathological changes associated with ROP in mice, including disruption of the membranous disks of photoreceptor outer segments and a decrease in electroretinographic amplitudes. Hdac6 transgenic mice exhibit similar ROP-related defects in retinal structures and functions and disassembly of photoreceptor cilia, whereas Hdac6 knockout mice are resistant to oxygen change-induced retinal defects. It is further shown that blocking HDAC6-mediated cilium disassembly by intravitreal injection of small-molecule compounds protect mice from ROP-associated retinal defects. The findings indicate that pharmacological targeting of the HDAC6-cilium axis may represent a promising strategy for the prevention of ROP.
