ESR13: AAV vector delivery targeting common pathways of disease in STGD1
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Iris Post
For as long as I can remember I’ve wanted to become a physician, because I wanted to help sick people get better. However, I’ve discovered that the science supporting medicine is at least as important as the physicians if you want to help ill people. I went to Radboud University in the Netherlands to pursue my Bachelor’s (Biology) and Master’s (Medical Biology) degrees. During the first research internship of my Master’s, under Prof. Frans Cremers, I first learned about Stargardt disease. Though my project back then was focused on splicing and not on Stargardt itself, my interest in the genetic background of the disease was founded. After a year in Australia for another research internship and travelling, I’m really looking forward to contribute to the StarT project. I’m very happy to have been chosen for ESR project 13: AAV vector delivery targeting common pathways of disease in STDG1 under Prof. Jane Farrar’s supervision. The goal of my project is to improve mitochondrial function within the retina to regulate oxygen consumption and ATP production as a therapy for STDG1 and I will do my very best to reach that goal. |
Abstract
There is growing evidence that many different genetic forms of IRD share common disease mechanisms. Indeed, similar disease processes between ABCA4-associated STGD1 and age related macular degeneration (AMD) have been proposed. Loss of the ABCA4 transporter involves, among other disease mechanisms, a build-up of di-retinoid-pyridinium-ethanolamine (A2E), a vitamin A dimer that becomes trapped in the retinal pigment epithelium (RPE). A2E is a major component of lipofuscin, a hallmark of human STGD1, the Abca4-/- mouse model and AMD. In turn it has been clearly demonstrated that the ATP production capacity of mitochondria in RPE cells is greatly diminished in the presence of A2E. Here, a novel therapeutic strategy for STGD1 is proposed: methods to sustain the mitochondrial function and ATP production capacity of RPE cells in the Abca4-/- mouse model of STGD1 and in cell models of disease generated as part of the planned research program. ESR13 will generate AAV vectors expressing components to augment mitochondrial function and modulate oxygen consumption rates and ATP production. Methods to assess mitochondrial function will be employed and potential beneficial effects of delivery of AAV vectors targeting such common pathways of disease will be evaluated in cell and animal models of STGD1.
There is growing evidence that many different genetic forms of IRD share common disease mechanisms. Indeed, similar disease processes between ABCA4-associated STGD1 and age related macular degeneration (AMD) have been proposed. Loss of the ABCA4 transporter involves, among other disease mechanisms, a build-up of di-retinoid-pyridinium-ethanolamine (A2E), a vitamin A dimer that becomes trapped in the retinal pigment epithelium (RPE). A2E is a major component of lipofuscin, a hallmark of human STGD1, the Abca4-/- mouse model and AMD. In turn it has been clearly demonstrated that the ATP production capacity of mitochondria in RPE cells is greatly diminished in the presence of A2E. Here, a novel therapeutic strategy for STGD1 is proposed: methods to sustain the mitochondrial function and ATP production capacity of RPE cells in the Abca4-/- mouse model of STGD1 and in cell models of disease generated as part of the planned research program. ESR13 will generate AAV vectors expressing components to augment mitochondrial function and modulate oxygen consumption rates and ATP production. Methods to assess mitochondrial function will be employed and potential beneficial effects of delivery of AAV vectors targeting such common pathways of disease will be evaluated in cell and animal models of STGD1.