[CCoE Notice] Cullen College Dissertation Defense Announcement - Ryan Crane

[Hutchinson, Inez A]

[Dissertation Defense Announcement at the Cullen College of Engineering]
Understanding The Visual And Auditory Defect In Ush2a Mouse Model

Ryan Crane
January 12, 2023; 3:00 PM - 5:00 PM (CST)
Location: SERC 2013
Zoom: https://urldefense.com/v3/__https://uh-edu-cougarnet.zoom.us/j/96931811237__;!!LkSTlj0I!A8KsKJF1Xod4GqGH5AVcZfIRS2Xxb5THBitMYFYfEDupsOk-iTp8YDiPZixawHiGdFk66JhpIaiD80svSQJbCvr0s9M$ 
Committee Chair:
Muna Naash, Ph.D.

Committee Members:
Muayyad Al-Ubaidi, Ph.D. | Andrew Groves, Ph.D. | Jun Yang, Ph.D. |
 Jason Porter, Ph.D. | Mario I. Romero-Ortega, Ph.D.
Abstract
Usher syndrome (USH) is the most common form of dual deafness and irreversible vision loss found in patients worldwide. USH2 is the most prevalently occurring sub type of clinical cases with patients suffering from congenital hearing loss and progressive vision loss beginning from adolescence. Mutations in USH2A (usherin) is the most common genetically mutated gene among USH patients. Usherin has been detected in the photoreceptors of the retina and in the developing inner ear cell stereocilia. The USH2A gene is very large and attempting gene therapy with conventional viral delivery is not easily attainable due to the limited payload capacity of commonly used Adeno-associated viruses (AAV).

To understand the mechanism underlying hearing and visual impairments, a knock in (KI) mouse model (Ush2adelG/delG) was developed using one of the most prevalent human mutations of USH2A, 2299delG. This model will be valuable to investigate possible delivery methods for USH2A. Retinal phenotype in the KI model was found to follow similar progression as patients, with a gradual loss of vison that became apparent at older ages, along with concomitant photoreceptor degeneration. Evaluating the cochlear phenotype in the KI showed congenital hearing loss and associated stereocilia of the inner hair cells were found to be disorganized. More in-depth analysis found that this was a result of mislocalization of the KI mutant protein and a subsequent mislocalization of its other USH2 interacting partners.

Following the analysis and verification of the KI model as a viable model for therapeutic testing, the next step was to develop a therapeutic approach for both the retina and cochlea. One major challenge of therapy for USH2 is its very large gene. Development of an alternative, non-viral delivery method is needed. We did so by encapsulating the therapeutic gene in using hyaluronic acid nanospheres (NSs). Delivery approaches for the eye, specifically targeting the retina, using NSs in conjunction with a small molecule, sulfotyrosine, have shown great promise and preliminary injections into the cochlea showed no major toxic effect.
[Engineered For What's Next]





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