HDAC6 adenovirus

Retinopathy of prematurity (ROP) is one of the leading causes of visual impairment and blindness in children. However, effective pharmacological interventions for ROP are still scarce. Histone deacetylase 6 (HDAC6)-mediated photoreceptor ciliary disassembly has recently been implicated as an early event in the pathogenesis of ROP. Here, researchers show that enhancing HDAC6 expression by intravitreal injection of adenovirus encoding HDAC6 induces typical pathological changes associated with ROP in mice, including destruction of photoreceptor outer segment membranous discs and reduced electroretinogram amplitude. Hdac6 transgenic mice exhibit ROP-associated retinal structural and functional defects and photoreceptor ciliary disassembly, while Hdac6 knockout mice are resistant to retinal defects caused by oxygen changes. Researchers further show that blocking HDAC6-mediated ciliary disassembly by intravitreal injection of small molecule compounds protects mice from retinal defects associated with ROP. These results suggest that drug targeting of the HDAC6-ciliary axis may be an effective strategy for preventing ROP.

To gain insight into the direct effects of HDAC6 on retinal structure and function, the researchers injected adenovirus encoding HDAC6 into mice intravitreally (Figure 1a, b). The experiment used eight-week-old mice to simulate patients with advanced ROP, accompanied by severe visual impairment. Compared with mice injected with control adenovirus, the a-wave (a-wave reflecting the general physiological activity of outer retinal photoreceptors) and b-wave (b-wave reflecting the activity of the inner layer of ON bipolar cells and Müller cells) of mice injected with HDAC6 adenovirus were reduced by more than 50% (Figure 1c-e). Therefore, overexpression of HDAC6 in the retina directly led to photoreceptor dysfunction. In the retinas of mice with high levels of HDAC6 expression, the thickness of the outer nuclear layer (ONL) was reduced by about 30%, indicating that overexpression of HDAC6 led to photoreceptor abnormalities (Figure 1f, g). Immunofluorescence microscopy showed that the membranous discs of rods and cones in mice injected with HDAC6 adenovirus were about 50% thinner than those in control mice (Figure 1h-j). The strength and length of ciliary axonemes in mice injected with HDAC6 adenovirus were reduced by approximately 70% and 50%, respectively (Figure 1k-m). These studies indicate that intravitreal injection of adenovirus encoding HDAC6 can directly induce typical pathological changes associated with retinopathy of prematurity (ROP), including photoreceptor cell dysfunction and damage to the membranous disks and ciliary axoneme.

Figure 1. Impairment of photoreceptor structures and functions in mice intravitreally injected with HDAC6 adenoviruses. (Ran J, et al., 2022)