ESR13: AAV vector delivery targeting common pathways of disease in STGD1
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Iris Post
My name is Iris and I am originally from the Netherlands. After a bachelors in Biology and a research master in Medical Biology, including internships in Nijmegen and Sydney, Australia, I got accepted to a PhD position at Trinity College Dublin as part of the MSCA ITN StarT. After 4 years of hard work, I successfully defended my PhD thesis titled: Modulation of mitochondrial function as a therapeutic strategy for Stargardt disease and an exploration of the genetic architecture of Stargardt disease in Ireland, in April 2024. During my PhD project my main focus was on the use of a yeast origin protein that augments mitochondrial function in various models of Stargardt disease as a potential treatment strategy. This protein, called NDI1, was engineered into a therapeutic viral vector and tested on various models of the disease. Here, we found that this therapeutic strategy had beneficial effects on a variety of parameters in disease models. Additionally, we recognised that it is important to understand the underlying molecular mechanisms of disease before future treatments can be applied to patients, so I created a large overview of the genetic causes of disease in all Irish individuals with a Stargardt phenotype. I am incredibly thankful for the opportunity to work within the StarT consortium. It has given me the chance to meet and work with some of the leading scientists in the field of ABCA4 and vision research. Additionally, the many courses and workshops provided by the consortium allowed me to broaden my scientific skills both inside and outside the research lab. The support given by this network had a very large and positive impact on my PhD journey as well and I am very grateful for that. |
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.
