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Doctoral Student Supervision (Jan 2008 - May 2021)
Vision loss, due to retinal degeneration, is one of the major disabilities in the developed world. Cell based therapeutics showed promising results in preventing retinal degenerations. Here, mesenchymal stem cells have been used to develop therapeutics for two different disorders. First, the innate paracrine activity of the Mesenchymal Stem Cells (MSCs) has been utilized to prevent neurodegeneration in a rodent model (S334ter-4) of Retinitis Pigmentosa. To deliver a significant number of cells to the rodent retina, a novel magnetic targeting approach was applied. The MSCs were pre-labelled with superparamagnetic iron oxide nanoparticles (SPIONs) and targeted to the eye by surgically placing a disc magnet in the orbit after systemic delivery. The magnetically guided MSCs provided better neuroprotection and functional responses (electroretinography and optokinetic tracking response) when compared to control and non-magnetic MSCs. The effect of magnetic nanoparticles on the paracrine secretion profile of MSCs was also analyzed. The concentration of the nanoparticles, used for the magnetic targeting study, had no significant effect on MSC’s paracrine activity; however, higher concentrations displayed varying effects for different factors. In the next project MSCs were employed as a vector for an ex vivo gene therapy approach for X linked retinoschisis (XLRS). MSCs were genetically modified to secrete an extracellular protein, retinoschisin (RS1), which is either nonfunctional or absent in XLRS. The RS1 expression from the MSCs was controlled in both constitutive (cMSC) and inducible (iMSC) manners. Cells, with both modifications, provided significant structural and functional benefits after intravitreal delivery in a RS1 knock-out mouse model when compared to unmodified MSCs, sham injection and no treatment controls. Among the two genetically modified cell lines, iMSC displayed better response compared to cMSC. These results from the MSC based therapeutic approaches in two different disease models show the potential of MSCs as a resourceful cell type for a number of retinal degenerations as well as diseases of other organs.