The Woodruff School

SUMMARY

Glaucoma, which affects almost 80 million people worldwide, is the main cause of irreversible blindness. The most common type, primary open angle glaucoma (POAG), causes gradual loss of vision by damaging retinal ganglion cells. The major risk factor for POAG is high intraocular pressure (IOP). Current clinical treatments for POAG aim to reduce IOP, but they often have low success rates. The trabecular meshwork (TM) is a key regulator of IOP and has been shown to undergo significant changes in POAG including a loss of cells. This motivates the regeneration or restoration of the TM as a potential treatment for POAG. While TM cell therapy has shown promise in the reversal of POAG pathology, previously developed cell delivery techniques have resulted in poor cell delivery efficiency which elevates the risk of tumorigenicity and immunogenicity and undermines therapeutic potential. In addition, a lack of comprehensive characterization of the treatment effects in an appropriate POAG model is a roadblock to clinical translation. We here tackled these shortcomings by: 1) using an optimized magnetic delivery method to significantly improve the specificity and efficiency of delivery of cells to the mouse TM, in turn reducing the risk of unwanted side-effects, and 2) employing this optimized method to test the therapeutic capabilities of two types of cells in a mutant myocilin mouse model of ocular hypertension, characterizing the morphological and functional benefits of the treatment. The central hypothesis of this work is that an optimized magnetically-driven TM cell therapy can lead to long-term clinically significant levels of IOP reduction while minimizing the risks associated with unwanted off-target cell delivery. This work resulted in the development of a novel magnetic TM cell therapy technique that outperformed those used previously. Employing this technique proved adipose-derived mesenchymal stem cells (hAMSC) and induced pluripotent stem cells differentiated towards a TM phenotype (iPSC-TM) to be effective in IOP lowering. Mesenchymal stem cells showed superior efficacy by stably lowering the IOP by 27% for 9 months, accompanied by increased cellularity in the conventional outflow pathway. These findings, bring magnetic TM cell therapy one step closer to clinical translation.

SUBJECT:	Ph.D. Dissertation Defense

BY:	Mohammad Reza Bahrani Fard

TIME:	Wednesday, November 29, 2023, 9:00 a.m.

PLACE:	IBB Building, 1128

TITLE:	Magnetic Steering to Save Sight: Trabecular Meshwork Cell Therapy as a Treatment for Primary Open Angle Glaucoma

COMMITTEE:	Dr. C. Ross Ethier, Chair (BME) Dr. Stanislav Emelianov (BME) Dr. Johnna Temenoff (BME) Dr. Cheng Zhu (ME/BME) Dr. Mark Prausnitz (ChE)

SUMMARY Glaucoma, which affects almost 80 million people worldwide, is the main cause of irreversible blindness. The most common type, primary open angle glaucoma (POAG), causes gradual loss of vision by damaging retinal ganglion cells. The major risk factor for POAG is high intraocular pressure (IOP). Current clinical treatments for POAG aim to reduce IOP, but they often have low success rates. The trabecular meshwork (TM) is a key regulator of IOP and has been shown to undergo significant changes in POAG including a loss of cells. This motivates the regeneration or restoration of the TM as a potential treatment for POAG. While TM cell therapy has shown promise in the reversal of POAG pathology, previously developed cell delivery techniques have resulted in poor cell delivery efficiency which elevates the risk of tumorigenicity and immunogenicity and undermines therapeutic potential. In addition, a lack of comprehensive characterization of the treatment effects in an appropriate POAG model is a roadblock to clinical translation. We here tackled these shortcomings by: 1) using an optimized magnetic delivery method to significantly improve the specificity and efficiency of delivery of cells to the mouse TM, in turn reducing the risk of unwanted side-effects, and 2) employing this optimized method to test the therapeutic capabilities of two types of cells in a mutant myocilin mouse model of ocular hypertension, characterizing the morphological and functional benefits of the treatment. The central hypothesis of this work is that an optimized magnetically-driven TM cell therapy can lead to long-term clinically significant levels of IOP reduction while minimizing the risks associated with unwanted off-target cell delivery. This work resulted in the development of a novel magnetic TM cell therapy technique that outperformed those used previously. Employing this technique proved adipose-derived mesenchymal stem cells (hAMSC) and induced pluripotent stem cells differentiated towards a TM phenotype (iPSC-TM) to be effective in IOP lowering. Mesenchymal stem cells showed superior efficacy by stably lowering the IOP by 27% for 9 months, accompanied by increased cellularity in the conventional outflow pathway. These findings, bring magnetic TM cell therapy one step closer to clinical translation.