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The Leber Congenital Amaurosis CEP29...

Minella, Andrea Louise.

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The Leber Congenital Amaurosis CEP290 Cat Model: Working Towards a Cure.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Leber Congenital Amaurosis CEP290 Cat Model: Working Towards a Cure./
作者:	Minella, Andrea Louise.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
面頁冊數:	216 p.
附註:	Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.
Contained By:	Dissertation Abstracts International78-10B(E).
標題:	Medicine. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10280955
ISBN:	9781369762525

The Leber Congenital Amaurosis CEP290 Cat Model: Working Towards a Cure.
Minella, Andrea Louise.

The Leber Congenital Amaurosis CEP290 Cat Model: Working Towards a Cure. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 216 p.

Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.

Thesis (Ph.D.)--Michigan State University, 2017.

Leber Congenital Amaurosis (LCA) is an early-onset and severe inherited retinal dystrophy. The most commonly implicated gene is the centrosomal 290kDa (CEP290) gene. There are currently no treatments for LCA CEP290. Animal models are integral for treatment safety and efficacy testing, with a feline model for CEP290 retinopathies showing promise for this purpose. This model has a spontaneous mutation in CEP290 resulting in a progressive retinal degeneration and vision loss. This mutation alters splicing and is predicted to result in a truncated protein. CEP290 is integrally involved in the transport within photoreceptor cells, localizing to the interconnecting cilium.

ISBN: 9781369762525Subjects--Topical Terms:

641104
Medicine.

The Leber Congenital Amaurosis CEP290 Cat Model: Working Towards a Cure.
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502 $a Thesis (Ph.D.)--Michigan State University, 2017.
520 $a Leber Congenital Amaurosis (LCA) is an early-onset and severe inherited retinal dystrophy. The most commonly implicated gene is the centrosomal 290kDa (CEP290) gene. There are currently no treatments for LCA CEP290. Animal models are integral for treatment safety and efficacy testing, with a feline model for CEP290 retinopathies showing promise for this purpose. This model has a spontaneous mutation in CEP290 resulting in a progressive retinal degeneration and vision loss. This mutation alters splicing and is predicted to result in a truncated protein. CEP290 is integrally involved in the transport within photoreceptor cells, localizing to the interconnecting cilium.
520 $a The CEP290 mutant cat ("rdAc") has a milder phenotype than the phenotype most commonly associated with CEP290 mutations in people. Understanding the reason for this milder phenotype was an important aim of this dissertation. We analyzed the wild-type and truncated mutant transcript levels and total CEP290 protein levels in cat retinal tissue across genotypes (wild-type, heterozygous, homozygous mutant). Our findings show that the milder phenotype in mutant cats is likely the result of low-level production of wild-type transcript and protein combined with production of truncated protein that we suspect retains some function. These measures can also serve as objective markers of disease progression or treatment success in future studies.
520 $a Further objective markers were investigated utilizing spectral-domain optical coherence tomography. By analyzing photoreceptor layer thickness (receptor plus/REC +) and the ellipsoid zone (EZ), a zone noted to change with disease in people, we showed that REC+ thickness and EZ integrity can be used as markers of disease progression. These findings support the cat as a CEP290 model, and show the affected cats have a degeneration with central retinal sparing as described in human patients.
520 $a We also developed an in vitro tool by developing primary fibroblast cell cultures from skin samples of CEP290 cats. We showed that cilia formation, which involves CEP290, can be induced, opening the door for future cilia studies. We assessed cilia length as an objective marker of disease, however, no difference was found in cilia length across genotypes. Utilizing this new tool, we tested a CRISPR/Cas-9 genome editing treatment in an attempt to replace the mutated region with a sequence that would direct splicing to the correct location. We achieved high efficiency transduction of CRISPR components, however, we failed to detect insertion of our chosen sequence.
520 $a As we work towards a treatment, it is imperative to develop an optimized method to deliver the treatment to feline photoreceptors. To achieve this aim we tested hybrid adeno-associated viral (AAV) vectors, the retinal viral vector of choice, in the wild-type feline retina. We showed that all serotypes studied, AAV2/2, 2/5, 2/8, and 2/9, transduce photoreceptor cells with AAV2/8 and 2/9 showing higher transduction and faster onset. Interestingly, we found more efficient transduction of cones than rods, an unusual finding that speaks to the need to use caution when extrapolating across species.
520 $a It is our hope that these data will help the scientific community move closer to treatments for CEP290 retinopathies. We have added to the understanding of the rdAc cat model and determined objective markers, supported the cat as a model, and have made progress towards a treatment.
590 $a School code: 0128.
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