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.
About the Researcher
The objective of the current proposal is to develop and validate cell specific, site-targeted, and therapeutically active mesenchymal stem cell (MSC)-derived exosomes (also known as extracellular vesicles or EVs) for prolonged neuroprotective effect from retinal glaucoma. My goal is to engineer EVs by tapping into their endocytotic and binding properties, thereby enhancing their delivery and action, thus preventing RGC and axonal loss.
I am a highly motivated, and well published research scientist with extensive expertise in translational research, in vivo pharmacological studies, inflammatory diseases, drug discovery, drug testing and validation. I joined Dr. Steven Roth’s lab in 2015 as a research assistant professor, and my research focus has since been on the prevention of retinal degenerative diseases. My prior work with inflammatory disease, specifically on endothelial vascular permeability, uniquely positions me to be able to successfully enact the proposed research. Alongside my specialization in biochemistry and molecular biology, additionally, I have extensive experience in both in vivo and in vitro disease model characterization, cell culture, and characterization of primary cell lines, and in planning, trouble shooting and data analytics. Over the last decade I have published 24 papers, a majority of them being in high-impact journals. My overall h-index is 15, with my 5-year h-index being 14. I also have extensive experience as a project lead and co-investigator on NIH funded PPG and RO1 grants. I take pride and joy in my role as a supervisor of lab personnel; in mentoring students, residents and fellows; and in making a powerful impact in the treatment of retinal disease through collaborations with other units and universities by expanding my knowledge base and continuously pushing the envelope towards better medical treatment.
Memories from my childhood are full of my aunt, the bravest and most beautiful woman I had ever known. From the early age of 18, she had suffered from blindness, and was never able to see again. I recall her sitting near a little radio listening to what was happening in the world around her, still stubbornly choosing to educate herself in spite of her new limitations, and then going on to educate others as well. I am saddened by the thought that there might have been a medical way to treat my aunt, allowing her to do more than just hear about the magnificent world around her. If she had better health care and treatment, her life might have been different. Sadly, my aunt was not the only one in my neighborhood who suffered from a lack of vision. This was thus something I grew up wanting to fix. While I did not become an optometrist or ophthalmologist, my interest was in no way deterred. Through my research I found the opportunity to focus on discovering novel therapeutic agents to alleviate the pain and suffering of disease, to develop novel antibiotics, and to initiate the development of promising drug candidates. Through my graduate and post-graduate work, I was involved in finding, testing, and validating drug targets and agents, which provided prevention and protection of individuals from disease. Through my current role in retinal-related research, I remember my dream of helping people who suffer from vision loss and retinal disease. I also feel a close connection to my aunt, who died at the age of 50, and I know that it is my responsibility to do research that will help people around the world who had to suffer a crippling disease similar to hers. The day I got my offer letter, I shared these thoughts with my dad, and we both were in tears.
I am increasingly passionate about my current retinal work: using exosomes from stem cells and, to help treat millions of people who suffer from severe vision loss. Funding for research is vital at every stage yet, it remains scarce. Having personally witnessed the crippling effect of blindness through my aunt, and the scarcity of research funding, it is donors like the BrightFocus Foundation supporting researchers like myself, providing the opportunity to continue and further research into novel treatment methods and eradication of crippling diseases.
First published on: August 29, 2018
Last modified on: March 27, 2020