Glaucoma is a progressive disease in which the optic nerve at the back of the eye is gradually damaged, and the visual field progressively narrows. The disease often develops asymptomatically, and patients are frequently unaware until a significant portion of their visual field is lost. In severe cases, it can lead to blindness.
One contributing factor is elevated pressure within the eye (intraocular pressure); however, there are also types of glaucoma that occur with normal eye pressure (normal-tension glaucoma). The cells that constitute the optic nerve (retinal ganglion cells) are part of the central nervous system, and once damaged and lost, they are unable to naturally regenerate. Consequently, at this point in time, it is deemed impossible to restore lost visual fields.
In fact, glaucoma is one of the leading causes of blindness worldwide, with an estimated 76 million people affected in 2020, and projected to affect over 111 million people by 2040.
Glaucoma Management Status and Challenges to be Addressed
Intraocular pressure management is currently the primary treatment.
Glaucoma is a disease in which intraocular pressure increases, causing progressive damage to the optic nerve. Therefore, current standard treatment focuses on lowering intraocular pressure to reduce the burden on the optic nerve. Key treatments include:
- Eye drops: Pharmacological agents for lowering intraocular pressure (e.g., prostaglandin analogues, beta-blockers, etc.)
- Laser treatment: Laser trabeculoplasty to increase aqueous humor outflow (fluid within the eye).
- Procedure: Trabeculotomy and shunt tube implantation to reduce intraocular pressure.
This treatment can delay the progression of visual deterioration, but currently there is no method to repair damaged optic nerves.
The limitation of an exclusive focus on development.
In fact, there are many cases where the visual field continues to gradually deteriorate even with ongoing treatment. For patients, a significant frustration remains: "all that is done is to prevent further progression, and lost visual field cannot be recovered."
In current medical practice, it is not possible to completely reverse optic nerve damage caused by glaucoma, and treatment is limited to symptomatic therapy that delays its progression.
For this reason, there is an urgent need for novel therapeutic approaches that can regenerate and repair the optic nerve itself.
Towards Optic Nerve Regeneration: Challenges of Stem Cell Therapy in Glaucoma
A regenerative approach that transcends conventional boundaries:
Historically, conventional glaucoma treatment focused on lowering intraocular pressure, with no method available to restore damaged optic nerves. To address this challenge, increasing attention is being given to stem cell therapy, a branch of regenerative medicine.
Stem cell therapy is a medical treatment method in which young and healthy cells, either autologous (from the patient themselves) or allogeneic (from a donor), are introduced into the body to promote the repair of damaged tissues or the restoration of function. In the context of glaucoma, there is also hope that this therapy could compensate for lost optic nerve cells and facilitate visual recovery.
Umbilical cord-derived MSCs attracting attention:
Among stem cells, mesenchymal stem cells (MSCs) are particularly promising in regenerative medicine within the field of ophthalmology. MSCs are found in bone marrow, adipose tissue, umbilical cord, and other sources, but particular attention is given to Wharton's Jelly-derived MSCs (WJ-MSCs), many of which are contained within Wharton's Jelly, a tissue within the umbilical cord.
- Collection Safety: The umbilical cord is naturally acquired during delivery, thus imposing no burden on the donor (newborn or mother).
- Youthful and active cells: With minimal age-related decline, they retain a high capacity for proliferation and differentiation even in long-term culture.
- Immunological privilege: Allogeneic transplantation is also not readily rejected immunologically.
- High safety: Risk of carcinogenesis is very low.
Given these characteristics, WJ-MSCs represent an ideal cell source for regenerative medicine and clinical research, with ongoing clinical applications worldwide. Indeed, recent research reviews also report that treatments utilizing umbilical cord MSCs have shown promising results for optic nerve disorders, including glaucoma.
Mechanism of Action of Stem Cells in Glaucoma Optic Nerve
Protecting nerve cells (neuroprotective effect):
MSCs abundantly secrete neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). These factors provide nutritional support to compromised retinal ganglion cells, thereby enhancing their survival rates. This action is analogous to supplying ample water and fertilizer to a wilting plant, promoting its revitalization. The "therapeutic cocktail" released by MSCs effectively ameliorates neuronal damage and provides robust support to these cells.
Alleviating inflammation (immunomodulatory effect):
MSC attenuate excessive inflammatory reactions and create a quiescent environment for the optic nerve. Specifically, they reduce the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6) while conversely promoting the secretion of anti-inflammatory cytokines (e.g., TGF-β, IL-10). Analogous to swiftly quelling a rampant blaze, MSC mitigate ocular inflammation and establish a milieu conducive to neuronal survival and function.
Enhances blood flow and delivers oxygen and nutrients.
Growth factors secreted by MSCs (e.g., VEGF, HGF) promote neovascularization around the optic nerve and enhance blood circulation. This ensures that nerve cells receive sufficient oxygen and nutrients, fostering a healthy environment to withstand damage. Analogously, this process is akin to introducing new irrigation channels to a drought-stricken field, enabling plants to flourish.
Potential for tissue repair and regeneration:
MSCs possess the capacity to differentiate into specific cell types as needed, assisting in the repair of damaged tissue. In glaucoma, regeneration is desired for two targets:
- Trabecular repair: If MSCs differentiate into trabecular cells that assist in aqueous humor outflow, there is potential to fundamentally improve intraocular pressure control.
- Retinal Ganglion Cell Regeneration: The potential exists for Mesenchymal Stem Cells (MSCs) to integrate with retinal visual neurons and establish new neural networks. Experimental findings indicate that stem cell-derived neurons have successfully engrafted into the retina, responded to light stimuli, and transmitted visual signals, thereby raising future expectations.
Expected Effects of Stem Cell Therapy for Glaucoma
Promising results demonstrated in animal models:
Previous research has demonstrated that stem cell therapy shows promising effects for glaucoma in animal models. When bone marrow-derived mesenchymal stem cells (MSCs) were injected into the eye, an increased survival rate of retinal ganglion cells (RGCs) was observed, and protection of optic nerve fibers (axons) was confirmed. In a separate study, it was reported that MSCs localized near the trabecular meshwork and improved aqueous humor outflow, consequently lowering intraocular pressure.
These findings demonstrate the potential of MSCs to protect the optic nerve and to control intraocular pressure from both directions.
Promising indicators in human clinical trials:
Optimism is also growing regarding the safety and efficacy of stem cell therapy in human clinical trials. In initial clinical trials, the transplantation of a stem cell-containing device into the eye was safely performed, and a trend of mild improvement in visual field tests was observed. Furthermore, the reduction in the thickness of the retinal nerve fiber layer (RNFL) was also curbed, suggesting the potential to halt the progression of optic nerve atrophy.
Furthermore, in a meta-analysis published in 2024, stem cell therapy was administered to 66 eyes of patients with optic nerve diseases (including glaucoma), and the results demonstrated a statistically significant mean improvement in vision. These findings are considered to introduce new possibilities to the previously held belief that "lost visual fields cannot be restored."
Expected Safety of Stem Cell Therapy for Glaucoma
Demonstrated security track record
Mesenchymal Stem Cell (MSC) therapy for glaucoma has demonstrated a favorable safety profile in current clinical studies. Umbilical cord-derived MSCs (UC-MSCs) exhibit low immunogenicity, making them less prone to rejection even when administered to allogeneic recipients. Indeed, in clinical trials conducted within the field of ophthalmology, no serious adverse events (such as infection or tumorigenesis) have been reported. UC-MSCs preserve cellular vitality, and the risk of genetic abnormalities or malignancy during the proliferative culture process has been confirmed as exceedingly low. Thus, MSCs are considered cells with an excellent safety profile, possessing inherent differentiation capacity without exhibiting uncontrolled plasticity.
Operational Security Management and Considerations
Stem cell therapy is a medical procedure, and it is crucial to administer it under appropriate clinical management. For intraocular cell injection, aseptic technique is necessary to prevent infection and inflammation in rare cases. These requirements are consistent with the protocols for existing treatments such as anti-VEGF injections. Following MSC administration, temporary ocular redness and blurred vision may occasionally be observed; however, most reactions are mild, transient, and resolve spontaneously.
Previous reports indicated no cases where vision significantly deteriorated due to stem cell therapy; conversely, many patients experienced positive changes post-surgery. To ensure safe treatment, it is crucial that treatment is administered under a professional management system at medical institutions where the quality management of stem cell cultivation and aseptic techniques are enhanced.
New Perspectives Brought by Regenerative Medicine
Stem cell therapy unlocks novel avenues in the field of optic nerve regeneration, an area previously considered unattainable. The era in which regenerative medicine offers renewed hope for visual function lost due to glaucoma is dawning. The inherent regenerative capacity and safety of stem cells broaden therapeutic options while simultaneously offering positive prospects for a multitude of patients.
Presently, researchers worldwide are diligently working towards clinical application, and significant progress is steadily being achieved. Glaucoma has long been considered an incurable disease; however, with a commitment to research and development, a glimmer of hope is beginning to emerge.
To patients and families affected by glaucoma and concerned about vision loss, please be aware that advancements in stem cell therapy are ongoing, and the future of this therapy holds significant promise. For further information regarding stem cell therapy for glaucoma or to consult about treatment eligibility, please contact a specialized medical institution or your treating physician.