In this application, we propose to investigate treatment using animal models of the genetically heterogeneous blinding disorder, Bardet-Biedl Syndrome (BBS). At least seventeen BBS genes have been reported to date. BBS is a pleiotropic disorder with the primary clinical features of pigmentary retinopathy, obesity, polydactyly, learning disabilities, renal abnormalities and hypogenitalism. BBS patients also have an increased incidence of hypertension, diabetes mellitus and congenital heart defects. The retinal degeneration of BBS is early onset and typically leads to blindness in the second decade of life. The blindness component of the BBS phenotype is the most concerning aspect of the disorder to patients and their families, and hence the component of BBS that we will focus on for treatment. Strategies for treating inherited forms of blindness include gene therapy, stem cell therapy, and pharmacological treatments. Gene therapy can theoretically target the primary gene defective in the specific patient, or alternatively target genes that modify the primary gene. Access to a number of different BBS animal models provides us with the opportunity to examine a variety of different approaches to treat the blindness component of BBS. In the proposed studies, we will utilize zebrafish to identify the specific genetic types of BBS that are most likey to be readily treatable with gene replacement therapy, and based on the zebrafish data, we will select at least six BBS mouse models to be treated with gene therapy (specific aim 1).
In specific aim 2, we will pursue the hypothesis that some forms of BBS can be treated by alteration of the expression of modifier genes. Finally, in specific aim 3, we hypothesize that specific molecular pathways modify BBS phenotypes. We will test this hypothesis by using pharmaceuticals to treat BBS mouse models targeting specific cellular pathways including apoptosis; endoplasmic reticulum (ER) stress and the unfolded protein response; chaperones; and PDGFR? signaling. Our studies will lead to a better understanding of cilia-related retinopathies; assist in classifying which of a number of treatments will best work, and provide an initial step in going from treatment of animal models to human treatment.

Public Health Relevance

The successful completion of this project will lead to insights into disease mechanisms causing inherited forms of blindness, as well as insights into common major human disorders including obesity, hypertension and diabetes. The results will potentially provide novel treatment strategies for Bardet-Biedl Syndrome, as well as other ciliopathies that lead to blindness.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Application #
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Shen, Grace L
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University of Iowa
Schools of Medicine
Iowa City
United States
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Sheffield, Isaac D; McGee, Mercedes A; Glenn, Steven J et al. (2018) Osteoarthritis-Like Changes in Bardet-Biedl Syndrome Mutant Ciliopathy Mice (Bbs1M390R/M390R): Evidence for a Role of Primary Cilia in Cartilage Homeostasis and Regulation of Inflammation. Front Physiol 9:708
Weihbrecht, Katie; Goar, Wesley A; Carter, Calvin S et al. (2018) Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove mouse model. PLoS One 13:e0192755
Haines, Jonathan L; Sheffield, Val C (2017) The molecular genetics of eye diseases. Hum Mol Genet 26:R1
Arafat, Maram; Har-Vardi, Iris; Harlev, Avi et al. (2017) Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet 54:633-639
Kawasaki, Makiri; Izu, Yayoi; Hayata, Tadayoshi et al. (2017) Bardet-Biedl syndrome 3 regulates the development of cranial base midline structures. Bone 101:179-190
Williams, Corey L; Uytingco, Cedric R; Green, Warren W et al. (2017) Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome. Mol Ther 25:904-916
Weihbrecht, Katie; Goar, Wesley A; Pak, Thomas et al. (2017) Keeping an Eye on Bardet-Biedl Syndrome: A Comprehensive Review of the Role of Bardet-Biedl Syndrome Genes in the Eye. Med Res Arch 5:
Hsu, Ying; Garrison, Janelle E; Kim, Gunhee et al. (2017) BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment. PLoS Genet 13:e1007057
Stone, Edwin M; Andorf, Jeaneen L; Whitmore, S Scott et al. (2017) Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology 124:1314-1331
Scott, Charles Anthony; Marsden, Autumn N; Rebagliati, Michael R et al. (2017) Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein. PLoS Genet 13:e1006936

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