Genomes and Genes
Treatment of a Complex Retinal Degenerative Syndrome
Principal Investigator: Val C Sheffield
Abstract: DESCRIPTION (provided by applicant): 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[unreadable] 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.
Funding Period: 1996-08-01 - 2018-06-30
more information: NIH RePORT
- Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia functionHsan Jan Yen
Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
Hum Mol Genet 15:667-77. 2006..These studies are the first to comprehensively compare the diverse group of BBS genes in parallel and demonstrate a common role in intracellular trafficking, indicating that BBS proteins are involved in general organelle trafficking...
- Genome-wide analysis of copy number variants in age-related macular degenerationKacie J Meyer
Interdisciplinary Genetics Program, University of Iowa, Iowa City, IA 52242, USA
Hum Genet 129:91-100. 2011..These and other candidate genes highlighted by this study deserve further scrutiny as sources of genetic risk for AMD...
- Inactivation of Bardet-Biedl syndrome genes causes kidney defectsDeng Fu Guo
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
Am J Physiol Renal Physiol 300:F574-80. 2011..These findings extend our understanding of the function of BBS proteins and emphasize the importance of these proteins in renal physiology...
- Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosomeChristopher J Westlake
Genentech, South San Francisco, CA 94080, USA
Proc Natl Acad Sci U S A 108:2759-64. 2011....
- Functional analysis of BBS3 A89V that results in non-syndromic retinal degenerationPamela R Pretorius
Department of Biology, Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa 52242, USA
Hum Mol Genet 20:1625-32. 2011..These data aid in our understanding of why patients with the BBS3 A89V missense mutation only present with isolated retinitis pigmentosa...
- Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1Masha Mazor
Department of Virology and Developmental Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
Am J Hum Genet 88:599-607. 2011..This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD...
- Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathwaysLiyun Sang
Genentech Inc, South San Francisco, CA 94080, USA
Cell 145:513-28. 2011..Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways...
- Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse modelCalvin S Carter
Graduate Program in Neuroscience, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Nat Med 18:1797-804. 2012..Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder...
- The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSomeXitiz Chamling
Department of Pediatrics, University of Iowa Interdisciplinary Program of Genetics, Iowa City, Iowa, United States of America
PLoS Genet 10:e1004083. 2014..These findings associate AZI1 with the BBS pathway. Our findings provide further insight into the regulation of BBSome ciliary trafficking and identify AZI1 as a novel BBS candidate gene. ..
- Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneityJulie C Sapp
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
Genet Med 12:623-7. 2010..The aim of this study was to derive locus-specific recurrence risk estimates for family members of a proband affected with Bardet-Biedl syndrome...
- Contrasting vascular effects caused by loss of Bardet-Biedl syndrome genesAndreas M Beyer
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Am J Physiol Heart Circ Physiol 299:H1902-7. 2010..In conclusion, these data implicate Bbs genes in the regulation of vascular function and demonstrate that disrupting Bbs2 and Bbs6 genes affect differentially the vascular function...
- Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11)Annie P Chiang
Department of Electrical Engineering, University of Iowa, Iowa City, IA 52242, USA
Proc Natl Acad Sci U S A 103:6287-92. 2006....
- Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10Dominic R A White
Department of Medical and Molecular Genetics, School of Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham, UK
Eur J Hum Genet 15:173-8. 2007....
- A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesisMaxence V Nachury
Genentech, Inc, South San Francisco, CA 94080, USA
Cell 129:1201-13. 2007..Conversely, preventing Rab8(GTP) production blocks ciliation in cells and yields characteristic BBS phenotypes in zebrafish. Our data reveal that BBS may be caused by defects in vesicular transport to the cilium...
- Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damageRuth E Swiderski
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA
Invest Ophthalmol Vis Sci 48:3329-40. 2007..To identify and characterize gene expression changes associated with photoreceptor cell loss in a Bbs4-knockout mouse model of retinal degeneration...
- A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesityRoger E Davis
Department of Pediatrics, Anatomy and Cell Biology, Radiology, University of Iowa, Iowa City, IA 52242, USA
Proc Natl Acad Sci U S A 104:19422-7. 2007....
- Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterningMarwan K Tayeh
Department of Pediatrics, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
Hum Mol Genet 17:1956-67. 2008..This study reveals an in vivo requirement for BBS function in limb bud patterning. Our results provide important new insights into the mechanism and biological significance of BBS...
- A BBSome subunit links ciliogenesis, microtubule stability, and acetylationAlexander V Loktev
Genentech, Inc, South San Francisco, CA 94080, USA
Dev Cell 15:854-65. 2008..BBSome-bound BBIP10 may therefore function to couple acetylation of axonemal microtubules and ciliary membrane growth...
- Requirement of Bardet-Biedl syndrome proteins for leptin receptor signalingSeongjin Seo
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa, IA 52242, USA
Hum Mol Genet 18:1323-31. 2009..Our data indicate that BBS proteins mediate LepR trafficking and that impaired LepR signaling underlies energy imbalance in BBS. These findings represent a novel mechanism for leptin resistance and obesity...
- Cartilage abnormalities associated with defects of chondrocytic primary cilia in Bardet-Biedl syndrome mutant miceAnjan P Kaushik
Department of Orthopaedic Surgery and Rehabilitation, University of Iowa, 200 Hawkins Drive, 01023 JPP, Iowa City, Iowa 52242, USA
J Orthop Res 27:1093-9. 2009..These data indicate that Bbs genes and their functions in the chondrocytic primary cilium are important for normal articular cartilage maintenance...
- A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytesKevin B Jones
Department of Orthopaedics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Proc Natl Acad Sci U S A 107:2054-9. 2010..These results explain prior modeling failures with the necessity for somatic LOH in a developmentally regulated cell type...
- The blind leading the obese: the molecular pathophysiology of a human obesity syndromeVal C Sheffield
Department of Pediatrics, Division of Medical Genetics, Howard Hughes Medical Institute, 4181 MERF, University of Iowa Iowa City, IA 52242, USA
Trans Am Clin Climatol Assoc 121:172-81; discussion 181-2. 2010..From the work described here, a common primary function of BBS proteins has emerged, specifically the mediation and regulation of microtubule-based intracellular transport...
- Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse modelKhristofor Agassandian
Department of Neuroscience, The University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
PLoS ONE 9:e93484. 2014....
- Complex Mechanisms in Bardet-Biedl Syndrome RetinopathyVal C Sheffield; Fiscal Year: 2013..The proposed studies have the potential to identify targets for treatment of BBS and other retinopathies. ..
- Intraflagellar Transport Proteins in MiceGregory J Pazour; Fiscal Year: 2013..This proposal seeks to understand the mechanism by which cilia are assembled and ultimately drive the identification of a treatment or cure for these diseases. ..
- Maternofetal Signaling and Lifelong ConsequencesKENT L R THORNBURG; Fiscal Year: 2013..Each of the 3 projects will use all cores. Core A is the Administrative Core, Core B is an Animal Core, Core C is the tissue Histopathology Core and Core D in the Ultrasound Imaging Core. ..
- Genetic analysis of the ciliopathies ARPKD and Meckel syndromePeter C Harris; Fiscal Year: 2013..These studies will be of diagnostic and prognostic importance in these disorders and help to understand the true complexity of simple genetic diseases. ..
- Expanding Excellence in Developmental Biology in OklahomaLinda F Thompson; Fiscal Year: 2013..abstract_text> ..
- Achromatopsia - Disease Mechanisms and Cone-Directed Gene TherapyAndras Komaromy; Fiscal Year: 2013..This research proposal focuses on the development of a new gene therapy to recover diseased cones and their function and to restore day-vision ..
- Mechanisms of assembly of photoreceptor G protein complexesBarry M Willardson; Fiscal Year: 2013..An understanding of the way these protein complexes are brought together is necessary to develop treatments that would allow the complexes to assemble and function despite the mutations. ..
- Photoreceptor Ciliopathies: RP2, KIF17 and NPHP5Wolfgang Baehr; Fiscal Year: 2013..Finally, AAV vectors will be designed to rescue the NPHP5-RP knockout mouse. ..
- Function of ciliary disease protein Retinitis Pigmentosa GTPase Regulator (RPGR)Hemant Khanna; Fiscal Year: 2013..Ultimately, such knowledge has the potential to inform the development of treatment modalities that will help to reduce the growing problem of retinal degenerative diseases in human beings. ..
- Novel genetics, pathobiology &therapy of nephronophthisis-related ciliopathiesFriedhelm Hildebrandt; Fiscal Year: 2013..It will allow development of animal models and novel therapeutic approaches to these degenerative diseases. ..
- Pathophysiology and Treatment of Fanconi's AnemiaMarkus Grompe; Fiscal Year: 2013..abstract_text> ..
- Molecular and Physiological Function of the Tubby Gene FamilyJuergen K Naggert; Fiscal Year: 2013....