REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

/pdf/bilateral-visual-improvement-with-unilateral-gene-therapy-3w6op0f50e.pdf

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.

The endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.

From endoplasmic reticulum stress to the inflammatory response.

Emerging role of Unfolded Protein Response (UPR) mediated proteotoxic apoptosis in diabetes.

Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats.

Genetic factors play an important role in the pathogenesis of diabetic retinopathy (DR). While many studies have focused on genes that increase susceptibility to DR, herein, we aimed to explore genes that confer DR resistance. Previously, we identified Hmg CoA reductase degradation protein 1 (SYVN1) as a putative DR protective gene via gene expression analysis. Transgenic mice overexpressing SYVN1 and wild-type (WT) mice with streptozotocin-induced diabetes were used in this experiment. Retinal damage and vascular leakage were investigated 6 months after induction of diabetes by histopathological and retinal cell apoptosis analyses and by retinal perfusion of fluorescein isothiocyanate-conjugated dextran. Compared with diabetic WT mice, diabetic SYVN1 mice had significantly more cells and reduced apoptosis in the retinal ganglion layer. Retinal vascular leakage was significantly lower in diabetic SYVN1 mice than in diabetic WT mice. The expression levels of endoplasmic reticulum (ER) stress-related, pro-inflammatory, and pro-angiogenic genes were also analyzed. Lower expression levels were observed in diabetic SYVN1 mice than in WT controls, suggesting that SYVN1 may play an important role in inhibiting ER stress, chronic inflammation, and vascular overgrowth associated with DR. Thus, these results strongly supported our hypothesis that SYVN1 confers DR resistance.

/pdf/experimental-study-of-the-protective-effects-of-syvn1-g9ztzr8gm8.pdf

Experimental study of the protective effects of SYVN1 against diabetic retinopathy

Background

To examine interactions between optic nerves.



Methods

A total of 24 Sprague–Dawley rats received unilateral intravitreal injections. The rats were equally divided into four groups: group A was administered an adeno-associated virus (AAV) carrying an exogenous gene (ND4; rAAV-ND4); group B, AAV carrying a green fluorescent protein (GFP; rAAV-GFP); group C, fluorogold (FG) nerve tracer dye; and group D, phosphate-buffered saline (PBS) as a control. Two weeks later, GFP expression was evaluated in both retinas and optic nerves of group B rats after frozen sectioning. The presence of FG was also evaluated in group C optic nerves by fluorescent microscopy after frozen sectioning. Four weeks after injection, ND4 expression was evaluated in both eyes of groups A and D using western blotting and immunofluorescence.



Results

FG was observed in the optic chiasm posterior segment along the optic nerve of injected eyes. Some FG reached the anterior optic nerve of the non-injected eye. GFP fluorescence was observed only in the retina of the injected eye but not in the contralateral retina or either optic nerve. ND4 expression was significantly different between injected and non-injected eyes but not between the non-injected eyes in groups A and D.



Conclusion

Unilaterally injected material can reach the contralateral optic nerve through axoplasmic transport. It is possible that this the only mechanism by which the optic nerves directly communicate.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ceo.12547

Chemical and material communication between the optic nerves in rats.

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Experimental study of the protective effects of SYVN1 against diabetic retinopathy

Chemical and material communication between the optic nerves in rats.