Researchers have unveiled promising new avenues for treating primary open angle glaucoma (POAG) and infantile aphakic glaucoma (IAG), two significant contributors to vision loss worldwide. The groundbreaking study, published on March 7, 2025, explores how adeno-associated virus (AAV) vectors can be used to regulate key molecular pathways involved in these conditions.
Approximately 76 million people suffer from POAG, making it the leading cause of irreversible blindness globally. Meanwhile, around 30,000 infants are diagnosed with cataracts annually, with surgery leading to secondary glaucoma, posing risks to their vision. The common link lies within the pathophysiology involving elevated intraocular pressure (IOP) and subsequent retinal ganglion cell death associated with these condition.
Central to the study's findings is transforming growth factor beta 2 (TGFβ2), which has been implicated in promoting fibrosis within the trabecular meshwork. This accumulation impairs aqueous humor drainage, leading to increased IOP, which is detrimental to RGCs—the nerve cells responsible for transmitting visual information.
The research team utilized the AAV-IKV vector to deliver gene therapies directly to the anterior segment of the eye. Notably, they created constructs expressing active TGFβ2, termed AAV-IKV-TGFβ2CS. When injected intracamerally, it resulted in significant fibrosis within the trabecular meshwork, leading to increased IOP and RGC death. "Intracameral injection of AAV-IKV expressing TGFβ2 led to fibrosis of the TM in mice and subsequent increase in IOP and RGC death," wrote the authors of the article.
On the other hand, the injection of AAV-IKV expressing human decorin showed reversal effects. Decorin acts as a negative regulator of TGFβ2, and its expression attenuated fibrosis, reduced IOP, and protected RGCs from death. The finding points to the potential of AAV-IKV-Decorin as a viable therapy for both POAG and IAG, stating, "Expression of human decorin from AAV-IKV vector attenuated fibrosis, IOP, and RGC death." This could represent a paradigm shift in how these conditions are treated.
The methodology involved injecting 0.52 × 10^9 AAV vector genomes intracamerally and measuring the subsequent IOP over 44 days. Remarkably, results indicated sustained reductions of IOP after introducing decorin, effectively stabilizing the IOP to levels seen within normal ranges. The researchers report, "AAV-IKV-Decorin may function as potential therapy for POAG and IAG respectively." The results demonstrate promise for treating challenging glaucoma cases.
Part of the study included testing the AAV delivery system’s performance as well. Non-human primates (NHPs) were involved where the AAV-IKV-GFP vector was injected, showing no detectable immune responses and confirming the vector’s safety and efficacy. Injecting 1.225 × 10^11 vector genomes led to observable expression patterns without significant inflammation or adverse reactions, promising for future clinical applications.
The researchers’ efforts shine light on the urgent need for alternative glaucoma therapies, especially as traditional treatments often fall short. This new gene therapy approach could offer continuous local production of therapeutics, addressing significant gaps left by systemic treatments and topical applications, which only manage the symptoms rather than target the underlying causes. The AAV-IKV vector enhances gene delivery to ocular tissues, with the potential to pave the way for innovative techniques to combat glaucoma.
The findings from this research can potentially reshape the future of glaucoma treatment, addressing the limitations of existing options.
Continued investigation will focus on long-term effects and possible clinical applications, aiming to change lives for millions on the brink of visual impairment.