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Novel Gene Therapy Strategies for Us...

Goldberg, Hannah Rae.

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Novel Gene Therapy Strategies for Usher Syndrome.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Novel Gene Therapy Strategies for Usher Syndrome./
Author:	Goldberg, Hannah Rae.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	162 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-09, Section: B.
Contained By:	Dissertations Abstracts International82-09B.
Subject:	Neurosciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28314382
ISBN:	9798582570936

Novel Gene Therapy Strategies for Usher Syndrome.
Goldberg, Hannah Rae.

Novel Gene Therapy Strategies for Usher Syndrome. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 162 p.

Source: Dissertations Abstracts International, Volume: 82-09, Section: B.

Thesis (Ph.D.)--Harvard University, 2021.

This item must not be sold to any third party vendors.

Hearing loss is the most prevalent neurological disorder in the world and has a profound impact on quality of life. Hearing loss can present on its own as non-syndromic, or together with other maladies as syndromic hearing loss. One of the most common forms of syndromic hearing loss is Usher Syndrome, which is a rare genetic multi-sensory loss disorder responsible for sensorineural hearing loss, blindness due to retinitis pigmentosa and vestibular areflexia. Extensive work over the past decades has elucidated the causative genes and pathogenic mutations underlying the three clinical Usher subtypes (USH-1, -2 and -3). Despite the emergence of etiological data and promising therapeutic candidates for hearing restoration, no biological treatment exists for these patients. In murine models of Usher syndrome type IID and autosomal recessive hearing loss 31 (DFNB31), harboring mutations in the protein whirlin, we developed a viral-mediated gene replacement strategy to reverse the auditory and balance dysfunction as well as disentangle the relative contributions of whirlin isoforms in stereocilia morphology and maintenance. Additionally, we have optimized a cutting-edge gene editing strategy to precisely target a pathogenic point mutation underlying Usher syndrome type IC in vitro. Using an RNA- programmable deaminase, we are able to efficiently reverse the disease-associated single nucleotide polymorphism. Lastly, we have developed and begun to characterize a CRISPR- generated swine model of Usher syndrome type IIA. In contrast to other established rodent models, these pigs more accurately recapitulate human anatomy, which may translate to the disease phenotype. This porcine model has the potential to address a major limitation in translational studies for genetic hearing loss.

ISBN: 9798582570936Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

Deafness

Novel Gene Therapy Strategies for Usher Syndrome.
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300 $a 162 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-09, Section: B.
500 $a Advisor: Holt, Jeffrey;Geleoc, Gwenaelle.
502 $a Thesis (Ph.D.)--Harvard University, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Hearing loss is the most prevalent neurological disorder in the world and has a profound impact on quality of life. Hearing loss can present on its own as non-syndromic, or together with other maladies as syndromic hearing loss. One of the most common forms of syndromic hearing loss is Usher Syndrome, which is a rare genetic multi-sensory loss disorder responsible for sensorineural hearing loss, blindness due to retinitis pigmentosa and vestibular areflexia. Extensive work over the past decades has elucidated the causative genes and pathogenic mutations underlying the three clinical Usher subtypes (USH-1, -2 and -3). Despite the emergence of etiological data and promising therapeutic candidates for hearing restoration, no biological treatment exists for these patients. In murine models of Usher syndrome type IID and autosomal recessive hearing loss 31 (DFNB31), harboring mutations in the protein whirlin, we developed a viral-mediated gene replacement strategy to reverse the auditory and balance dysfunction as well as disentangle the relative contributions of whirlin isoforms in stereocilia morphology and maintenance. Additionally, we have optimized a cutting-edge gene editing strategy to precisely target a pathogenic point mutation underlying Usher syndrome type IC in vitro. Using an RNA- programmable deaminase, we are able to efficiently reverse the disease-associated single nucleotide polymorphism. Lastly, we have developed and begun to characterize a CRISPR- generated swine model of Usher syndrome type IIA. In contrast to other established rodent models, these pigs more accurately recapitulate human anatomy, which may translate to the disease phenotype. This porcine model has the potential to address a major limitation in translational studies for genetic hearing loss.
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