RGC Neuroprotection Following Optic Nerve Trauma Mediated By Intranasal Delivery of Amnion Cell Secretome

Abstract

PurposeIntranasally delivered ST266, the biological, proteinaceous secretome of amnion-derived multipotent progenitor cells, reduces retinal ganglion cell (RGC) loss, optic nerve inflammation, and demyelination in experimental optic neuritis. This unique therapy and novel administration route delivers numerous cytokines and growth factors to the eye and optic nerve, suggesting a potential to also treat other optic neuropathies. Thus, ST266-mediated neuroprotection was examined following traumatic optic nerve injury.MethodsOptic nerve crush injury was surgically induced in C57BL/6J mice. Mice were treated daily with intranasal PBS or ST266. RGC function was assessed by optokinetic responses (OKRs), RGCs were counted, and optic nerve sections were stained with luxol fast blue and anti-neurofilament antibodies to assess myelin and RGC axon damage.ResultsIntranasal ST266 administered daily for 5 days, beginning at the time that a 1-second optic nerve crush was performed, significantly attenuated OKR decreases. Furthermore, ST266 treatment reduced damage to RGC axons and myelin within optic nerves, and blocked RGC loss. Following a 4-second optic nerve crush, intranasal ST266 increased RGC survival and showed a trend toward reduced RGC axon and myelin damage. Ten days following optic nerve crush, ST266 prevented myelin damage, while also inducing a trend toward increased RGC survival and visual function.ConclusionsST266 significantly attenuates traumatic optic neuropathy. Neuroprotective effects of this unique combination of biologic molecules observed here and previously in optic neuritis suggest potential broad application for preventing neuronal damage in multiple optic nerve disorders. Furthermore, results support intranasal delivery as a novel, noninvasive therapeutic modality for eyes and optic nerves.

Effects of Varying Intranasal Treatment Regimens in ST266-Mediated Retinal Ganglion Cell Neuroprotection

“…The current studies demonstrated that intranasal delivery of the novel biologic therapy ST266 promoted beneficial effects on multiple features of experimental optic neuritis, including attenuating vision loss, promoting RGC survival, and reducing the degree of optic nerve inflammation and demyelination. Results are consistent with prior studies of optic neuritis (33), as well as neuroprotective effects mediated by ST266 in a model of traumatic optic neuropathy (36). Importantly, the current results suggest that once daily ST266 dosing is sufficient to promote maximal neuroprotective effects, as twice daily treatment led to equivalent outcomes.…”

“…ST266 (Noveome Biotherapeutics, Inc., Pittsburgh, PA) was aliquoted and stored at −20 °C. A fresh aliquot was thawed and warmed to room temperature each day and administered to the mice as a single 6 μL drop placed in the nose (33,36). Mice were grouped and treated once or twice with one drop of ST266, PBS, STM100 (the cell culture medium used to culture AMP cells and collect ST266 protein secretions), or 0.5% human serum albumin (HSA) in PBS intranasally beginning after the onset of optic neuritis (day 15 postimmunization).…”

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

“…Intranasal administration of the secretome from multipotent stem/progenitor cells has been proposed as a strategy for treating other diseases, such as retinal ganglion cell loss [ 75 , 76 ], multiple sclerosis [ 77 ], Alzheimer’s disease [ 78 ], and Parkinson’s disease [ 79 ], including recently, alcohol and nicotine consumption [ 58 ]. In all these models, MSC-S has shown anti-inflammatory and antioxidant effects, also improving neurodevelopment and memory function.…”

Neuroprotection mediated by ST266 requires full complement of proteins secreted by amnion-derived multipotent progenitor cells

“…Intranasally-delivered ST266 protects against vision loss, preserves retinal ganglion cells (RGCs), and decreases inflammation and demyelination of the optic nerve in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS [ 4 , 6 ]. These effects are selective for EAE optic neuritis, with the highest concentrations of ST266 proteins accumulating preferentially in the eye and optic nerve, with no effects observed in suppressing EAE lesions in the spinal cords of the same mice [ 4 ].…”