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Retina regeneration. new strategies to treat inherited retinal dystrophies
Retina regeneration. new strategies to treat inherited retinal dystrophies
Our sense of vision largely defines who we are as individuals and as a society, by shaping our perception and allowing us to communicate beyond language barriers. Blinding diseases such as inherited retinal dystrophies therefore have severe mental and socio-economic consequences, which sparked multiple efforts to halt and reverse degeneration in these patients. This thesis set out to advance different therapeutic strategies that are both clinically established or under investigation, for patients at all disease stages. To address the needs of patients with early- to mid-stage retinal degeneration, two potent AAV capsids were engineered to deliver genetic cargo via a less invasive administration route, namely intravitreal injection. The properties of these novel vectors were verified in mouse, dog, non-human primate and human retina, showing a widespread transduction of photoreceptors across species. To demonstrate the potential of these vectors in gene supplementation therapy, a mouse model of achromatopsia was treated, resulting in the rescue of cone photoreceptor function and showing signs of tissue rejuvenation. For patients with late-stage retinal degeneration, two therapeutic approaches were explored that would either confer light-sensing abilities to the remaining retinal network or replenish the missing neuronal population by reprogramming retinal glia. Regarding the former, a universal method for isolating ON bipolar cells was established that would enable the development of novel vectors for delivering optogenetic tools in a cell-specific manner. Regarding the latter, a series of exploratory experiments were performed showing the potential of pioneering factors to directly reprogram retinal microglia into neurons, highlighting the potential of regenerating the retina from within. This body of work was able to optimise existing strategies to treat inherited retinal dystrophies and offered new solutions for patients with so far limited therapeutic options.
retina, AAV, vector, screening, intravitreal, achromatopsia, degeneration, reprogramming, optogenetics, vision, FACS, ON-bipolar
Pavlou, Marina
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Pavlou, Marina (2021): Retina regeneration: new strategies to treat inherited retinal dystrophies. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Our sense of vision largely defines who we are as individuals and as a society, by shaping our perception and allowing us to communicate beyond language barriers. Blinding diseases such as inherited retinal dystrophies therefore have severe mental and socio-economic consequences, which sparked multiple efforts to halt and reverse degeneration in these patients. This thesis set out to advance different therapeutic strategies that are both clinically established or under investigation, for patients at all disease stages. To address the needs of patients with early- to mid-stage retinal degeneration, two potent AAV capsids were engineered to deliver genetic cargo via a less invasive administration route, namely intravitreal injection. The properties of these novel vectors were verified in mouse, dog, non-human primate and human retina, showing a widespread transduction of photoreceptors across species. To demonstrate the potential of these vectors in gene supplementation therapy, a mouse model of achromatopsia was treated, resulting in the rescue of cone photoreceptor function and showing signs of tissue rejuvenation. For patients with late-stage retinal degeneration, two therapeutic approaches were explored that would either confer light-sensing abilities to the remaining retinal network or replenish the missing neuronal population by reprogramming retinal glia. Regarding the former, a universal method for isolating ON bipolar cells was established that would enable the development of novel vectors for delivering optogenetic tools in a cell-specific manner. Regarding the latter, a series of exploratory experiments were performed showing the potential of pioneering factors to directly reprogram retinal microglia into neurons, highlighting the potential of regenerating the retina from within. This body of work was able to optimise existing strategies to treat inherited retinal dystrophies and offered new solutions for patients with so far limited therapeutic options.