Project Description Narrative:
Vision loss is a dreaded affliction that U.S. residents fear more than loss of hearing, memory, or speech. Currently, retinal diseases leading to the death of visual circuitry neurons results in incurable blindness. Retinal diseases impact all ages of the population, ranging from congenital retinal dystrophies to adult onset, age-related diseases, such as macular degeneration (AMD) and glaucoma. Wisconsin closely mirrors the nation-wide prevalence rates of people living with visual acuity loss (U.S.: 2.17%; Wisconsin: 1.75%) and blindness (U.S.: 0.33%; Wisconsin: 0.29%). When separated by age, the mean prevalence rate of visual afflictions begins to significantly increase in people aged 60 years or over, a trend that is also observed in Wisconsin with some counties reaching higher levels than the national average (up to 13%). Those at greatest risk within this aged population include racial and ethnic minority groups, women, and people with less education, experiencing poverty, with underlying health conditions, or living in rural areas. By 2050, visual acuity loss and blindness statistics are set to nearly double in Wisconsin (2017: 1.75%; 2050 prediction: 3.36%), due to the anticipated increase in life expectancy.
Development of new preventative therapies targeted to the early stages of age-related retinal diseases will be crucial to combat future social and economic burdens and improve the lives of these vulnerable patient populations. While restorative cell therapies show incredible promise in treating late-stage retinal diseases, more early-stage interventions to preserve vision are needed. Gene therapy and neuroprotective compound applications help to fill this need depending on the retinal disease type, but currently there are no generic therapies targeted to promoting neuronal function. Early indicators of retinal disease in patients with AMD and glaucoma prior to irreversible cell death include synapse loss and retinal circuitry re-wiring. Therefore, correction of neuron function by promoting healthy synapse regeneration during early stages of disease progression holds therapeutic promise. Synapse formation (synaptogenesis) and function is highly dependent on the interactions of proteins produced by glial cells, such as astrocytes. In a disease modeling context, the lead researcher on this project recently demonstrated using in vitro human cell cultures that synaptic activity could be rescued in patient diseased neurons by the addition of astrocytes derived from healthy individuals. This suggests that restoring glia-mediated interactions with neurons can facilitate healthy synapse formation and function in disease. While these interactions are well-characterized for retinal astrocytes which are restricted to the nerve fiber layer to support ganglion cell synapses, the synaptogenic potential of the other major type of retinal glial cell, Müller glia, currently remains understudied.
As the only glial cell to directly contact all cell and synaptic layers of the retina, further demonstration of Müller glia-mediated mechanisms of synaptogenesis could be harnessed in developing future early intervention therapies to promote function across multiple retinal neurons and treat a myriad of retinal diseases, including age-related retinal degeneration. In this project, the lead researcher will leverage her current technical training and prior graduate expertise in retinal organoid differentiation to launch a research program focused on glial-mediated synaptic support in the retina. The project will establish the retinal organoid culture protocol at MCW and begin collecting preliminary data for larger grant applications.