Novel Cell-Free Treatment of Glaucoma

Retinal ganglion cell death and axonal loss are hallmark events leading to glaucoma and neuroprotection of retina by regeneration, or prevention of cells from dying, are key factors and major public health necessities. Our objective is to study the use of extracellular vehicles (EVs), tiny particles secreted by mesenchymal stem cells, as a treatment for glaucoma induced cell death. Delivering the EVs specifically in to the retina and prolonging the effect, are major limitations reducing the treatment efficacy. Therefore, our study is focused on engineering modified targeted EVs for retina-specific neuroprotective action for treating glaucoma.

Protecting the eye against retinal neuronal cell loss is the key factor in developing treatment strategies for glaucoma. This project specifically focuses on using human bone marrow stem cell-derived exosomes (30-150nm size particles) as novel therapeutic agents to protect retinal neurons affected in glaucoma. Towards this aim, I will modify exosomes to target, then be delivered specifically to retinal ganglion cells (RGCs) for prolonged action in the retina to decrease the complexities leading to glaucoma.

The onset of glaucoma is manifest by neuronal cell death and neuroinflammation, resulting in retinal neuronal cell and axonal loss. Preventing against RGC death is key in the development of preventative and/or therapeutic agents for glaucoma treatment. Stem cell-based retinal cell replacement is a highly encouraged approach for neuroprotection and/or regeneration, though immune response, aberrant/ectopic growth, and surgical complications limit its promise. Mounting evidence suggests that most mesenchymal stem cell (MSC) effects are from factors secreted from the cells and likely mediated by extracellular vesicles (EVs). The advantages of using EVs are that they do not require donor matching, are easily stored, and are non-proliferative, thereby proving suitable for precision-based medicine. It may thus be possible to avoid the limitations and complications of stem cell therapy in the eye through the use of EVs. Our central hypothesis is that MSC-derived EVs prevent the loss of retinal cells and their function. This project has two parts based on the two aims. In Aim 1, we will determine the mechanisms of MSC-EV uptake by RGCs. In Aim 2, we will develop modified EVs for targeted delivery.

These studies will provide the basis for clinical translation with novel engineered EVs for retina-specific neuroprotective action. We also predict EV biology will be vertically advanced by engineering EV membranes, leading to tissue-specific targeting of EVs in retina. Successful completion of this project also will advance the development of versatile, safe, and effective modified and target-specific EVs that are biomimetic, disease-specific, non-immunogenic and efficient therapeutic tools. Translational significance is the high likelihood of effecting changes in the delivery of molecules for retinal disease.