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<strong><span style="font-size:18.0pt;font-family:"Calibri",sans-serif;color:#C8102E">Identification and Application of Novel Therapeutic Targets for
<i>PRPH2</i>-Associated Disorders</span></strong><o:p></o:p></p>
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<strong><span style="font-size:13.5pt;font-family:"Calibri",sans-serif;color:black">Christian Rutan Woods</span></strong><o:p></o:p></p>
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<span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">May 25, 2023; 9:15 AM - 11:15 AM (CST)<br>
Location: W205 (Engineering Bldg 2)<br>
Zoom: </span><a href="https://urldefense.com/v3/__https://uh-edu-cougarnet.zoom.us/j/91337707043__;!!LkSTlj0I!EKMzwlwkpL7Bmc6B55JocnTSf81EMvZZEbQdRgi8x4sFnobPXGxRXYxiQh4DByGtwGk-6K3rjCSj6Ar4XxCYMJWHFDI$"><span style="font-size:10.5pt;font-family:"Arial",sans-serif">https://uh-edu-cougarnet.zoom.us/j/91337707043</span></a><o:p></o:p></p>
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<strong><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">Committee Chair:</span></strong><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black"><br>
Muayyad R. Al-Ubaidi, Ph.D.</span><o:p></o:p></p>
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<strong><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">Committee Members:</span></strong><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black"><br>
Muna Naash, Ph.D. | Tianfu Wu, Ph.D. | James B. Hurley, Ph.D. | Bin Guo, Ph.D.</span><o:p></o:p></p>
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<strong><span style="font-family:"Arial",sans-serif;color:#C8102E">Abstract</span></strong><o:p></o:p></p>
<p><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">Mutations in the photoreceptor specific tetraspanin Peripherin-2 (<i>PRPH2</i>) are some of the most pervasive pathogenic inherited retinal disease mutations with over 200 identified.
Lack of an FDA approved treatment, numerous low prevalence mutations, and complex pathogenic mechanisms make it imperative to identify a ubiquitous therapeutic target. We attempted to identify pan-mutation therapeutic strategies by targeting outer segment
(OS) structural abnormalities associated with <i>Prph2 </i>mutations as well as investigating disruptions in the metabolic symbiosis between the retina and RPE.
</span><o:p></o:p></p>
<p><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">In attempts to ameliorate OS structural abnormalities, we investigated reducing rhodopsin (RHO) levels as a ubiquitous therapeutic target in
<i>Prph2<sup>K153Δ /+</sup></i><sup> </sup>and <i>Prph2<sup>Y141C/+</sup></i><sup>
</sup>mice. We hypothesized increased ratios of RHO to PRPH2 play a role in <i>PRPH2</i>-associated pathogenesis as mutations decrease functional PRPH2 levels. Proof-of-concept studies utilized partial genetic ablation to reduce RHO and improve this ratio in
favor of PRPH2. Reduction improved OS ultrastructure resulting in increased photoreceptor physiological responses in a mutation-independent manner across multiple time points.</span><o:p></o:p></p>
<p><span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">Investigating the clinical relevance of this strategy, we employed an antisense oligonucleotide (ASO),
<i>mRho</i> ASO1, to reduce RHO levels in <i>Prph2<sup>Y141C /+</sup></i><sup> </sup>
mice. ASO intervention at multiple time points was able to successfully recapitulate the previously observed photoreceptor functional and ultrastructural improvements. However, no differences were seen in the inner retina b-wave functional responses. Strikingly,
we observed increased photoreceptor survival following early intervention and reduced immune cell infiltration following late intervention. These results show modulation of OS structural abnormalities to be a viable option for amelioration of retinal degeneration.
</span><o:p></o:p></p>
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<span style="font-size:10.5pt;font-family:"Arial",sans-serif;color:black">In parallel studies, we investigated the role of metabolic dysregulation in
<i>Prph2</i>-associated disease pathogenesis. Despite the fact PRPH2 is photoreceptor specific, mutations result in secondary RPE defects. We performed untargeted metabolomics analysis on retinas and eyecups from
<i>Prph2<sup>K153Δ /+</sup></i><sup> </sup>and <i>Prph2<sup>Y141C /+</sup></i><sup>
</sup>mice to evaluate changes in metabolite steady-state levels. The retina and RPE are known to possess a complementary metabolic relationship imperative to their health. We report disease stage dependent perturbations in metabolite levels essential to this
homeostasis. These findings present multiple targets for future evaluation to better understand the role of metabolic abnormalities in
<i>Prph2</i>-associated disease progression and secondary RPE defects..</span><o:p></o:p></p>
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<p class="MsoNormal"><span style="font-size:13.5pt;font-family:"Arial",sans-serif;color:black"><img border="0" width="600" height="82" style="width:6.25in;height:.8541in" id="Picture_x0020_2" src="cid:image002.png@01D988A2.165CF2D0" alt="Engineered For What's Next"></span><o:p></o:p></p>
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