Gene Therapy for Glaucoma: Overcoming Limitations of Traditional Therapeutics

Glaucoma is a chronic neurodegenerative disease characterized by the deterioration of the optic nerve and the progressive loss of retinal ganglion cells (RGCs), making it a leading cause of irreversible blindness worldwide. This neurodegenerative process is characterized by the apoptotic death of neurons whose axons constitute the optic nerve, leading to permanent visual field deficits. Although current standard-of-care therapies-including pharmacological, laser, and surgical interventions-mainly target reducing intraocular pressure (IOP), their clinical efficacy remains limited due to side effects, inconsistent outcomes, and a failure to halt neurodegeneration. Therefore, there is an urgent need for novel therapeutic frameworks that move beyond symptomatic pressure control toward molecular intervention. Gene therapy has become one of the most promising directions due to its ability to offer new perspectives on the future management of glaucoma. Viral vectors, such as adeno-associated virus (AAV), can deliver therapeutic payloads directly to ocular tissues, potentially enabling long-term transgene expression after a single administration. This review discusses the pathophysiology of glaucoma and the shortcomings of available therapies, highlighting opportunities for next-generation genetic treatments. We group the possible options of gene therapy into two different paths, which are to regulate the flow of aqueous humor through the trabecular meshwork and the ciliary body, and directly provide neuroprotection to RGCs. The former involves genetic modulation of the conventional outflow pathway to restore physiological homeostasis, while the latter focuses on enhancing neurons' intrinsic survival signals by expressing neurotrophic factors or anti-apoptotic genes. Importantly, this review uniquely integrates these molecular targets with appropriate animal models, providing a comprehensive strategic framework for translating genetic discoveries into clinical applications.