Treatment of a Complex Retinal Degenerative Syndrome

Summary

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

Top Publications

  1. ncbi Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function
    Hsan Jan Yen
    Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
    Hum Mol Genet 15:667-77. 2006
  2. pmc Genome-wide analysis of copy number variants in age-related macular degeneration
    Kacie J Meyer
    Interdisciplinary Genetics Program, University of Iowa, Iowa City, IA 52242, USA
    Hum Genet 129:91-100. 2011
  3. pmc Inactivation of Bardet-Biedl syndrome genes causes kidney defects
    Deng Fu Guo
    Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
    Am J Physiol Renal Physiol 300:F574-80. 2011
  4. pmc Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome
    Christopher J Westlake
    Genentech, South San Francisco, CA 94080, USA
    Proc Natl Acad Sci U S A 108:2759-64. 2011
  5. pmc Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration
    Pamela R Pretorius
    Department of Biology, Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa 52242, USA
    Hum Mol Genet 20:1625-32. 2011
  6. pmc Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1
    Masha 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
  7. pmc Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways
    Liyun Sang
    Genentech Inc, South San Francisco, CA 94080, USA
    Cell 145:513-28. 2011
  8. pmc Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model
    Calvin S Carter
    Graduate Program in Neuroscience, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
    Nat Med 18:1797-804. 2012
  9. pmc The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome
    Xitiz Chamling
    Department of Pediatrics, University of Iowa Interdisciplinary Program of Genetics, Iowa City, Iowa, United States of America
    PLoS Genet 10:e1004083. 2014
  10. pmc Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneity
    Julie C Sapp
    National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
    Genet Med 12:623-7. 2010

Detail Information

Publications26

  1. ncbi Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function
    Hsan 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...
  2. pmc Genome-wide analysis of copy number variants in age-related macular degeneration
    Kacie 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...
  3. pmc Inactivation of Bardet-Biedl syndrome genes causes kidney defects
    Deng 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...
  4. pmc Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome
    Christopher J Westlake
    Genentech, South San Francisco, CA 94080, USA
    Proc Natl Acad Sci U S A 108:2759-64. 2011
    ....
  5. pmc Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration
    Pamela 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...
  6. pmc Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1
    Masha 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...
  7. pmc Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways
    Liyun 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...
  8. pmc Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model
    Calvin 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...
  9. pmc The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome
    Xitiz 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. ..
  10. pmc Recurrence risks for Bardet-Biedl syndrome: Implications of locus heterogeneity
    Julie 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...
  11. pmc Contrasting vascular effects caused by loss of Bardet-Biedl syndrome genes
    Andreas 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...
  12. pmc 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
    ....
  13. ncbi Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10
    Dominic 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
    ....
  14. ncbi A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis
    Maxence 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...
  15. ncbi Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage
    Ruth 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...
  16. pmc A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity
    Roger 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
    ....
  17. pmc Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning
    Marwan 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...
  18. ncbi A BBSome subunit links ciliogenesis, microtubule stability, and acetylation
    Alexander 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...
  19. pmc Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling
    Seongjin 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...
  20. pmc Cartilage abnormalities associated with defects of chondrocytic primary cilia in Bardet-Biedl syndrome mutant mice
    Anjan 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...
  21. pmc A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes
    Kevin 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...
  22. pmc The blind leading the obese: the molecular pathophysiology of a human obesity syndrome
    Val 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...
  23. pmc Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model
    Khristofor Agassandian
    Department of Neuroscience, The University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 9:e93484. 2014
    ....

Research Grants30

  1. Complex Mechanisms in Bardet-Biedl Syndrome Retinopathy
    Val C Sheffield; Fiscal Year: 2013
    ..The proposed studies have the potential to identify targets for treatment of BBS and other retinopathies. ..
  2. Intraflagellar Transport Proteins in Mice
    Gregory 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. ..
  3. Maternofetal Signaling and Lifelong Consequences
    KENT 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. ..
  4. Genetic analysis of the ciliopathies ARPKD and Meckel syndrome
    Peter 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. ..
  5. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  6. Achromatopsia - Disease Mechanisms and Cone-Directed Gene Therapy
    Andras 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 ..
  7. Mechanisms of assembly of photoreceptor G protein complexes
    Barry 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. ..
  8. Photoreceptor Ciliopathies: RP2, KIF17 and NPHP5
    Wolfgang Baehr; Fiscal Year: 2013
    ..Finally, AAV vectors will be designed to rescue the NPHP5-RP knockout mouse. ..
  9. 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. ..
  10. Novel genetics, pathobiology &therapy of nephronophthisis-related ciliopathies
    Friedhelm Hildebrandt; Fiscal Year: 2013
    ..It will allow development of animal models and novel therapeutic approaches to these degenerative diseases. ..
  11. Pathophysiology and Treatment of Fanconi's Anemia
    Markus Grompe; Fiscal Year: 2013
    ..abstract_text> ..
  12. Molecular and Physiological Function of the Tubby Gene Family
    Juergen K Naggert; Fiscal Year: 2013
    ....