Identification and Application of Novel Therapeutic Targets for PRPH2-Associated Disorders

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dc.contributor.advisorAl-Ubaidi, Muayyad R.
dc.contributor.committeeMemberNaash, Muna I.
dc.contributor.committeeMemberWu, Tianfu
dc.contributor.committeeMemberHurley, James B.
dc.contributor.committeeMemberGuo, Bin
dc.creatorRutan Woods, Christian Tyler
dc.creator.orcid0009-0003-9061-6545
dc.date.accessioned2024-01-20T20:46:58Z
dc.date.createdAugust 2023
dc.date.issued2023-08
dc.date.updated2024-01-20T20:46:59Z
dc.description.abstractMutations in the photoreceptor specific tetraspanin Peripherin-2 (PRPH2) 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 OS structural abnormalities associated with Prph2 mutations as well as investigating disruptions in the metabolic symbiosis between the retina and RPE. In attempts to ameliorate OS structural abnormalities, we investigated reducing rhodopsin (RHO) levels as a ubiquitous therapeutic target in Prph2K153Δ /+ and Prph2Y141C/+ mice. We hypothesized increased ratios of RHO to PRPH2 play a role in PRPH2-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. Investigating the clinical relevance of this strategy, we employed an antisense oligonucleotide (ASO), mRho ASO1, to reduce RHO levels in Prph2Y141C /+ 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. In parallel studies, we investigated the role of metabolic dysregulation in Prph2-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 Prph2K153Δ /+ and Prph2Y141C /+ 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 Prph2-associated disease progression and secondary RPE defects.
dc.description.departmentBiomedical Engineering, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/15920
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectInherited retinal diseases
dc.subjectPeripherin-2
dc.subjectRhodopsin
dc.subjectAntisense oligonucleotide
dc.subjectRetina
dc.subjectPhotoreceptors
dc.subjectRetinal pigment epithelium
dc.subjectMetabolomics
dc.subjectMetabolism
dc.titleIdentification and Application of Novel Therapeutic Targets for PRPH2-Associated Disorders
dc.type.dcmitext
dc.type.genreThesis
dcterms.accessRightsThe full text of this item is not available at this time because the student has placed this item under an embargo for a period of time. The Libraries are not authorized to provide a copy of this work during the embargo period.
local.embargo.lift2025-08-01
local.embargo.terms2025-08-01
thesis.degree.collegeCullen College of Engineering
thesis.degree.departmentBiomedical Engineering, Department of
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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