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Therapeutic perspectives for structural and functional abnormalities of cilia

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Abstract

Ciliopathies are a group of hereditary disorders that result from structural or functional abnormalities of cilia. Recent intense research efforts have uncovered the genetic bases of ciliopathies, and our understanding of the assembly and functions of cilia has been improved significantly. Although mechanism-specific therapies for ciliopathies have not yet received regulatory approval, the use of innovative therapeutic modalities such as oligonucleotide therapy, gene replacement therapy, and gene editing in addition to symptomatic treatments are expected to provide valid treatment options in the near future. Moreover, candidate chemical compounds for developing small molecule drugs to treat ciliopathies have been identified. This review introduces the key features of cilia and ciliopathies, and summarizes the advances as well as the challenges that remain with the development of therapies for treating ciliopathies.

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References

  1. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11:331–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ishikawa H, Marshall WF (2011) Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol 12:222–234

    Article  CAS  PubMed  Google Scholar 

  3. Carvalho-Santos Z, Azimzadeh J, Pereira-Leal JB, Bettencourt-Dias M (2011) Evolution: tracing the origins of centrioles, cilia, and flagella. J Cell Biol 194:165–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fisch C, Dupuis-Williams P (2011) Ultrastructure of cilia and flagella—back to the future! Biol Cell 103:249–270

    Article  PubMed  Google Scholar 

  5. Rosenbaum JL, Witman GB (2002) Intraflagellar transport. Nat Rev Mol Cell Biol 3:813–825

    Article  CAS  PubMed  Google Scholar 

  6. Reiter JF, Leroux MR (2017) Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol 18:533–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Garcia-Gonzalo FR, Reiter JF (2012) Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J Cell Biol 197:697–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Reiter JF, Blacque OE, Leroux MR (2012) The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep 13:608–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Czarnecki PG, Shah JV (2012) The ciliary transition zone: from morphology and molecules to medicine. Trends Cell Biol 22:201–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Awata J, Takada S, Standley C, Lechtreck KF, Bellve KD, Pazour GJ, Fogarty KE, Witman GB (2014) NPHP4 controls ciliary trafficking of membrane proteins and large soluble proteins at the transition zone. J Cell Sci 127:4714–4727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Basiri ML, Ha A, Chadha A, Clark NM, Polyanovsky A, Cook B, Avidor-Reiss T (2014) A migrating ciliary gate compartmentalizes the site of axoneme assembly in Drosophila spermatids. Curr Biol 24:2622–2631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chih B, Liu P, Chinn Y, Chalouni C, Komuves LG, Hass PE, Sandoval W, Peterson AS (2011) A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 14:61–72

    Article  CAS  PubMed  Google Scholar 

  13. Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ, Garcia-Verdugo JM, Katsanis N, Hildebrandt F, Reiter JF (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43:776–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE, Yoder BK, Leroux MR (2011) MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 192:1023–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fliegauf M, Benzing T, Omran H (2007) When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8:880–893

    Article  CAS  PubMed  Google Scholar 

  16. Fowkes ME, Mitchell DR (1998) The role of preassembled cytoplasmic complexes in assembly of flagellar dynein subunits. Mol Biol Cell 9:2337–2347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Salathe M (2007) Regulation of mammalian ciliary beating. Annu Rev Physiol 69:401–422

    Article  CAS  PubMed  Google Scholar 

  18. Heuser T, Raytchev M, Krell J, Porter ME, Nicastro D (2009) The dynein regulatory complex is the nexin link and a major regulatory node in cilia and flagella. J Cell Biol 187:921–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Warner FD (1976) Ciliary inter-microtubule bridges. J Cell Sci 20:101–114

    CAS  PubMed  Google Scholar 

  20. Horani A, Ferkol TW, Dutcher SK, Brody SL (2016) Genetics and biology of primary ciliary dyskinesia. Paediatr Respir Rev 18:18–24

    PubMed  Google Scholar 

  21. Ibanez-Tallon I, Pagenstecher A, Fliegauf M, Olbrich H, Kispert A, Ketelsen UP, North A, Heintz N, Omran H (2004) Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet 13:2133–2141

    Article  CAS  PubMed  Google Scholar 

  22. Tilley AE, Walters MS, Shaykhiev R, Crystal RG (2015) Cilia dysfunction in lung disease. Annu Rev Physiol 77:379–406

    Article  CAS  PubMed  Google Scholar 

  23. Halbert SA, Patton DL, Zarutskie PW, Soules MR (1997) Function and structure of cilia in the fallopian tube of an infertile woman with Kartagener’s syndrome. Hum Reprod 12:55–58

    Article  CAS  PubMed  Google Scholar 

  24. Inaba K, Mizuno K (2016) Sperm dysfunction and ciliopathy. Reprod Med Biol 15:77–94

    Article  CAS  PubMed  Google Scholar 

  25. Dasgupta A, Amack JD (2016) Cilia in vertebrate left-right patterning. Philos Trans R Soc Lond B Biol Sci 371:1–9

    Article  Google Scholar 

  26. Pennekamp P, Menchen T, Dworniczak B, Hamada H (2015) Situs inversus and ciliary abnormalities: 20 years later, what is the connection? Cilia 4:1

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hildebrandt F, Benzing T, Katsanis N (2011) Ciliopathies. N Engl J Med 364:1533–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wheway G, Parry DA, Johnson CA (2014) The role of primary cilia in the development and disease of the retina. Organogenesis 10:69–85

    Article  PubMed  Google Scholar 

  29. Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11:273–284

    Article  CAS  PubMed  Google Scholar 

  30. Goldberg AF, Moritz OL, Williams DS (2016) Molecular basis for photoreceptor outer segment architecture. Prog Retin Eye Res 55:52–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. McEwen DP, Jenkins PM, Martens JR (2008) Olfactory cilia: our direct neuronal connection to the external world. Curr Top Dev Biol 85:333–370

    Article  CAS  PubMed  Google Scholar 

  32. Flannery RJ, French DA, Kleene SJ (2006) Clustering of cyclic-nucleotide-gated channels in olfactory cilia. Biophys J 91:179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jenkins PM, McEwen DP, Martens JR (2009) Olfactory cilia: linking sensory cilia function and human disease. Chem Senses 34:451–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ciuman RR (2011) Auditory and vestibular hair cell stereocilia: relationship between functionality and inner ear disease. J Laryngol Otol 125:991–1003

    Article  CAS  PubMed  Google Scholar 

  35. Jones C, Chen P (2008) Primary cilia in planar cell polarity regulation of the inner ear. Curr Top Dev Biol 85:197–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hudspeth AJ, Jacobs R (1979) Stereocilia mediate transduction in vertebrate hair cells (auditory system/cilium/vestibular system). Proc Natl Acad Sci USA 76:1506–1509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jones C, Roper VC, Foucher I, Qian D, Banizs B, Petit C, Yoder BK, Chen P (2008) Ciliary proteins link basal body polarization to planar cell polarity regulation. Nat Genet 40:69–77

    Article  CAS  PubMed  Google Scholar 

  38. Gerdes JM, Davis EE, Katsanis N (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137:32–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lancaster MA, Gleeson JG (2009) The primary cilium as a cellular signaling center: lessons from disease. Curr Opin Genet Dev 19:220–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Eggenschwiler JT, Anderson KV (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol 23:345–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hassounah NB, Bunch TA, McDermott KM (2012) Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling. Clin Cancer Res 18:2429–2435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Eguether T, Hahne M (2018) Mixed signals from the cell’s antennae: primary cilia in cancer. EMBO Rep 19:1–15

    Article  CAS  Google Scholar 

  43. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DYR, Reiter JF (2005) Vertebrate smoothened functions at the primary cilium. Nature 437:1018–1021

    Article  CAS  PubMed  Google Scholar 

  44. Lancaster MA, Schroth J, Gleeson JG (2011) Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. Nat Cell Biol 13:700-U173

    Google Scholar 

  45. Ezratty EJ, Stokes N, Chai S, Shah AS, Williams SE, Fuchs E (2011) A role for the primary cilium in notch signaling and epidermal differentiation during skin development. Cell 145:1129–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, Cassell MD, Thedens DR, Keppler-Noreuil KM, Nopoulos P, Nishimura DY, Searby CC, Bugge K, Sheffield VC (2012) Abnormal development of NG2+ PDGFR-alpha+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18:1797–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, Beyer T, Janusch H, Hamann C, Godel M, Muller K, Herbst M, Hornung M, Doerken M, Kottgen M, Nitschke R, Igarashi P, Walz G, Kuehn EW (2010) Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol 12:1115–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhou J (2009) Polycystins and primary cilia: primers for cell cycle progression. Annu Rev Physiol 71:83–113

    Article  CAS  PubMed  Google Scholar 

  49. Patel A, Honore E (2010) Polycystins and renovascular mechanosensory transduction. Nat Rev Nephrol 6:530–538

    Article  CAS  PubMed  Google Scholar 

  50. Gradilone SA, Masyuk AI, Splinter PL, Banales JM, Huang BQ, Tietz PS, Masyuk TV, Larusso NF (2007) Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proc Natl Acad Sci USA 104:19138–19143

    Article  PubMed  PubMed Central  Google Scholar 

  51. Masyuk AI, Huang BQ, Radtke BN, Gajdos GB, Splinter PL, Masyuk TV, Gradilone SA, LaRusso NF (2013) Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am J Physiol Gastrointest Liver Physiol 304:G1013–G1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Madhivanan K, Aguilar RC (2014) Ciliopathies: the trafficking connection. Traffic 15:1031–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hildebrandt F, Attanasio M, Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20:23–35

    Article  CAS  PubMed  Google Scholar 

  54. Drivas TG, Bennett J (2014) CEP290 and the primary cilium. Adv Exp Med Biol 801:519–525

    Article  PubMed  Google Scholar 

  55. Sleigh MA (1981) Primary ciliary dyskinesia. Lancet 2:476

    Article  CAS  PubMed  Google Scholar 

  56. Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW (2013) Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med 188:913–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Popatia R, Haver K, Casey A (2014) Primary ciliary dyskinesia: an update on new diagnostic modalities and review of the literature. Pediatr Allergy Immunol Pulmonol 27:51–59

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mirra V, Werner C, Santamaria F (2017) Primary ciliary dyskinesia: an update on clinical aspects, genetics, diagnosis, and future treatment strategies. Front Pediatr 5:135

    Article  PubMed  PubMed Central  Google Scholar 

  59. Snell WJ, Pan JM, Wang Q (2004) Cilia and flagella revealed: from flagellar assembly in Chlamydomonas to human obesity disorders. Cell 117:693–697

    Article  CAS  PubMed  Google Scholar 

  60. Hoefele J, Wolf MT, O’Toole JF, Otto EA, Schultheiss U, Deschenes G, Attanasio M, Utsch B, Antignac C, Hildebrandt F (2007) Evidence of oligogenic inheritance in nephronophthisis. J Am Soc Nephrol 18:2789–2795

    Article  CAS  PubMed  Google Scholar 

  61. Simms RJ, Eley L, Sayer JA (2009) Nephronophthisis. Eur J Hum Genet 17:406–416

    Article  CAS  PubMed  Google Scholar 

  62. Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, McDonald R, Eddy A, Chance PF, Glass IA (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 75:82–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425:628–633

    Article  CAS  PubMed  Google Scholar 

  64. Zaghloul NA, Katsanis N (2009) Mechanistic insights into Bardet–Biedl syndrome, a model ciliopathy. J Clin Investig 119:428–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369:1287–1301

    Article  PubMed  Google Scholar 

  66. Grantham JJ (2008) Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med 359:1477–1485

    Article  CAS  PubMed  Google Scholar 

  67. Ward CJ, Yuan D, Masyuk TV, Wang X, Punyashthiti R, Whelan S, Bacallao R, Torra R, LaRusso NF, Torres VE, Harris PC (2003) Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet 12:2703–2710

    Article  CAS  PubMed  Google Scholar 

  68. Kim I, Fu Y, Hui K, Moeckel G, Mai W, Li C, Liang D, Zhao P, Ma J, Chen XZ, George AL Jr, Coffey RJ, Feng ZP, Wu G (2008) Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J Am Soc Nephrol 19:455–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S (2013) Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 45:1004–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Perugorria MJ, Masyuk TV, Marin JJ, Marzioni M, Bujanda L, LaRusso NF, Banales JM (2014) Polycystic liver diseases: advanced insights into the molecular mechanisms. Nat Rev Gastroenterol Hepatol 11:750–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wills ES, Roepman R, Drenth JP (2014) Polycystic liver disease: ductal plate malformation and the primary cilium. Trends Mol Med 20:261–270

    Article  CAS  PubMed  Google Scholar 

  72. Mikolajczyk AE, Te HS, Chapman AB (2017) Gastrointestinal manifestations of autosomal-dominant polycystic kidney disease. Clin Gastroenterol Hepatol 15:17–24

    Article  PubMed  Google Scholar 

  73. Gunay-Aygun M (2009) Liver and kidney disease in ciliopathies. Am J Med Genet C Semin Med Genet 151C:296–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mockel A, Perdomo Y, Stutzmann F, Letsch J, Marion V, Dollfus H (2011) Retinal dystrophy in Bardet–Biedl syndrome and related syndromic ciliopathies. Prog Retin Eye Res 30:258–274

    Article  CAS  PubMed  Google Scholar 

  75. Estrada-Cuzcano A, Roepman R, Cremers FP, den Hollander AI, Mans DA (2012) Non-syndromic retinal ciliopathies: translating gene discovery into therapy. Hum Mol Genet 21:R111–R124

    Article  CAS  PubMed  Google Scholar 

  76. Zhao Y, Hong DH, Pawlyk B, Yue G, Adamian M, Grynberg M, Godzik A, Li T (2003) The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci USA 100:3965–3970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen Y, Zhang Q, Shen T, Xiao X, Li S, Guan L, Zhang J, Zhu Z, Yin Y, Wang P, Guo X, Wang J, Zhang Q (2013) Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis. Investig Ophthalmol Vis Sci 54:4351–4357

    Article  CAS  Google Scholar 

  78. Koenekoop RK (2004) An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol 49:379–398

    Article  PubMed  Google Scholar 

  79. Stone EM (2007) Leber congenital amaurosis—a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol 144:791–811

    Article  CAS  PubMed  Google Scholar 

  80. Cideciyan AV, Rachel RA, Aleman TS, Swider M, Schwartz SB, Sumaroka A, Roman AJ, Stone EM, Jacobson SG, Swaroop A (2011) Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum Mol Genet 20:1411–1423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lee JE, Gleeson JG (2011) Cilia in the nervous system: linking cilia function and neurodevelopmental disorders. Curr Opin Neurol 24:98–105

    Article  PubMed  PubMed Central  Google Scholar 

  82. Oud MM, Lamers IJ, Arts HH (2017) Ciliopathies: genetics in pediatric medicine. J Pediatr Genet 6:18–29

    Article  CAS  PubMed  Google Scholar 

  83. Guemez-Gamboa A, Coufal NG, Gleeson JG (2014) Primary cilia in the developing and mature brain. Neuron 82:511–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Moore SJ, Green JS, Fan Y, Bhogal AK, Dicks E, Fernandez BA, Stefanelli M, Murphy C, Cramer BC, Dean JC, Beales PL, Katsanis N, Bassett AS, Davidson WS, Parfrey PS (2005) Clinical and genetic epidemiology of Bardet–Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study. Am J Med Genet A 132A:352–360

    Article  PubMed  PubMed Central  Google Scholar 

  85. Han YM, Kang GM, Byun K, Ko HW, Kim J, Shin MS, Kim HK, Gil SY, Yu JH, Lee B, Kim MS (2014) Leptin-promoted cilia assembly is critical for normal energy balance. J Clin Investig 124:2193–2197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Baala L, Audollent S, Martinovic J, Ozilou C, Babron MC, Sivanandamoorthy S, Saunier S, Salomon R, Gonzales M, Rattenberry E, Esculpavit C, Toutain A, Moraine C, Parent P, Marcorelles P, Dauge MC, Roume J, Le Merrer M, Meiner V, Meir K, Menez F, Beaufrere AM, Francannet C, Tantau J, Sinico M, Dumez Y, MacDonald F, Munnich A, Lyonnet S, Gubler MC, Genin E, Johnson CA, Vekemans M, Encha-Razavi F, Attie-Bitach T (2007) Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet 81:170–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Szymanska K, Berry I, Logan CV, Cousins SR, Lindsay H, Jafri H, Raashid Y, Malik-Sharif S, Castle B, Ahmed M, Bennett C, Carlton R, Johnson CA (2012) Founder mutations and genotype-phenotype correlations in Meckel–Gruber syndrome and associated ciliopathies. Cilia 1:18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zaki MS, Sattar S, Massoudi RA, Gleeson JG (2011) Co-occurrence of distinct ciliopathy diseases in single families suggests genetic modifiers. Am J Med Genet A 155A:3042–3049

    Article  PubMed  Google Scholar 

  89. Ak S (1904) Uber einem Fall von Bronchiectasie bei einem Patienten mit Situs inversus viscerum. Berliner klinische Wochenschrift 41:139–141

    Google Scholar 

  90. Pennarun G, Escudier E, Chapelin C, Bridoux AM, Cacheux V, Roger G, Clement A, Goossens M, Amselem S, Duriez B (1999) Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet 65:1508–1519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hayes D Jr, Reynolds SD, Tumin D (2016) Outcomes of lung transplantation for primary ciliary dyskinesia and Kartagener syndrome. J Heart Lung Transplant 35:1377–1378

    Article  PubMed  Google Scholar 

  92. Chapman AB, Stepniakowski K, Rahbari-Oskoui F (2010) Hypertension in autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis 17:153–163

    Article  PubMed  PubMed Central  Google Scholar 

  93. Schrier RW (2009) Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 20:1888–1893

    Article  PubMed  Google Scholar 

  94. Schrier RW (2016) ACE inhibitors, left ventricular mass and renal cyst growth in ADPKD. Pharmacol Res 114:166–168

    Article  CAS  PubMed  Google Scholar 

  95. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS, TT Investigators (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367:2407–2418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O, Investigators RT (2017) Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med 377:1930–1942

    Article  CAS  PubMed  Google Scholar 

  97. Tesar V, Ciechanowski K, Pei Y, Barash I, Shannon M, Li R, Williams JH, Levisetti M, Arkin S, Serra A (2017) Bosutinib versus placebo for autosomal dominant polycystic kidney disease. J Am Soc Nephrol 28:3404–3413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sweeney WE, Frost P, Avner ED (2017) Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease. World J Nephrol 6:188–200

    Article  PubMed  PubMed Central  Google Scholar 

  99. Clement K, Biebermann H, Farooqi IS, Van der Ploeg L, Wolters B, Poitou C, Puder L, Fiedorek F, Gottesdiener K, Kleinau G, Heyder N, Scheerer P, Blume-Peytavi U, Jahnke I, Sharma S, Mokrosinski J, Wiegand S, Muller A, Weiss K, Mai K, Spranger J, Gruters A, Blankenstein O, Krude H, Kuhnen P (2018) MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med 24:551–555

    Article  CAS  PubMed  Google Scholar 

  100. Kuhnen P, Clement K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Gruters A, Krude H (2016) Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med 375:240–246

    Article  CAS  PubMed  Google Scholar 

  101. Dias MF, Joo K, Kemp JA, Fialho SL, da Silva Cunha A Jr, Woo SJ, Kwon YJ (2018) Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res 63:107–131

    Article  CAS  PubMed  Google Scholar 

  102. Guadagni V, Novelli E, Piano I, Gargini C, Strettoi E (2015) Pharmacological approaches to retinitis pigmentosa: a laboratory perspective. Prog Retin Eye Res 48:62–81

    Article  CAS  PubMed  Google Scholar 

  103. Browd SR, Ragel BT, Gottfried ON, Kestle JR (2006) Failure of cerebrospinal fluid shunts: part I: obstruction and mechanical failure. Pediatr Neurol 34:83–92

    Article  PubMed  Google Scholar 

  104. Wang J, Lon HK, Lee SL, Burckart GJ, Pisetsky DS (2015) Oligonucleotide-based drug development: considerations for clinical pharmacology and immunogenicity. Ther Innov Regul Sci 49:861–868

    PubMed  Google Scholar 

  105. Delihas N, Rokita SE, Zheng P (1997) Natural antisense RNA/target RNA interactions: possible models for antisense oligonucleotide drug design. Nat Biotechnol 15:751–753

    Article  CAS  PubMed  Google Scholar 

  106. Rayburn ER, Zhang R (2008) Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible? Drug Discov Today 13:513–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, Chin W, Tribble DL, McGowan M (2012) Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 126:2283–2292

    Article  CAS  PubMed  Google Scholar 

  108. Syed YY (2016) Eteplirsen: first global approval. Drugs 76:1699–1704

    Article  CAS  PubMed  Google Scholar 

  109. Markowitz JA, Singh P, Darras BT (2012) Spinal muscular atrophy: a clinical and research update. Pediatr Neurol 46:1–12

    Article  PubMed  Google Scholar 

  110. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC, ES Group (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377:1723–1732

    Article  CAS  PubMed  Google Scholar 

  111. Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, Iannaccone ST, Kirschner J, Kuntz NL, Saito K, Shieh PB, Tulinius M, Mazzone ES, Montes J, Bishop KM, Yang Q, Foster R, Gheuens S, Bennett CF, Farwell W, Schneider E, De Vivo DC, Finkel RS, CS Group (2018) Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 378:625–635

    Article  CAS  PubMed  Google Scholar 

  112. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet 79:556–561

    Article  Google Scholar 

  113. Parfitt DA, Lane A, Ramsden CM, Carr AJ, Munro PM, Jovanovic K, Schwarz N, Kanuga N, Muthiah MN, Hull S, Gallo JM, da Cruz L, Moore AT, Hardcastle AJ, Coffey PJ, Cheetham ME (2016) Identification and correction of mechanisms underlying inherited blindness in human iPSC-derived optic cups. Cell Stem Cell 18:769–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dulla K, Aguila M, Lane A, Jovanovic K, Parfitt DA, Schulkens I, Chan HL, Schmidt I, Beumer W, Vorthoren L, Collin RWJ, Garanto A, Duijkers L, Brugulat-Panes A, Semo M, Vugler AA, Biasutto P, Adamson P, Cheetham ME (2018) Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c.2991+ 1655A>G LCA10 models. Mol Ther Nucleic Acids 12:730–740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cideciyan AV, Jacobson SG, Drack AV, Ho AC, Charng J, Garafalo AV, Roman AJ, Sumaroka A, Han IC, Hochstedler MD, Pfeifer WL, Sohn EH, Taiel M, Schwartz MR, Biasutto P, Wit W, Cheetham ME, Adamson P, Rodman DM, Platenburg G, Tome MD, Balikova I, Nerinckx F, Zaeytijd J, Van Cauwenbergh C, Leroy BP, Russell SR (2019) Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med 25:225–228

    Article  CAS  PubMed  Google Scholar 

  116. Lennox KA, Behlke MA (2011) Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther 18:1111–1120

    Article  CAS  PubMed  Google Scholar 

  117. Havens MA, Hastings ML (2016) Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res 44:6549–6563

    Article  PubMed  PubMed Central  Google Scholar 

  118. Karras JG, Crosby JR, Guha M, Tung D, Miller DA, Gaarde WA, Geary RS, Monia BP, Gregory SA (2007) Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice. Am J Respir Cell Mol Biol 36:276–285

    Article  CAS  PubMed  Google Scholar 

  119. Tanaka M, Nyce JW (2001) Respirable antisense oligonucleotides: a new drug class for respiratory disease. Respir Res 2:5–9

    Article  CAS  PubMed  Google Scholar 

  120. Oberbauer R, Schreiner GF, Biber J, Murer H, Meyer TW (1996) In vivo suppression of the renal Na+/Pi cotransporter by antisense oligonucleotides. Proc Natl Acad Sci USA 93:4903–4906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sugo T, Terada M, Oikawa T, Miyata K, Nishimura S, Kenjo E, Ogasawara-Shimizu M, Makita Y, Imaichi S, Murata S, Otake K, Kikuchi K, Teratani M, Masuda Y, Kamei T, Takagahara S, Ikeda S, Ohtaki T, Matsumoto H (2016) Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release 237:1–13

    Article  CAS  PubMed  Google Scholar 

  122. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, Booten SL, Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze EE, Seth PP (2014) Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 42:8796–8807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kotterman MA, Schaffer DV (2014) Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 15:445–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Scott LJ (2015) Alipogene tiparvovec: a review of its use in adults with familial lipoprotein lipase deficiency. Drugs 75:175–182

    Article  CAS  PubMed  Google Scholar 

  125. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM (2017) Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390:849–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Campa C, Gallenga CE, Bolletta E, Perri P (2017) The role of gene therapy in the treatment of retinal diseases: a review. Curr Gene Ther 17:194–213

    Article  CAS  PubMed  Google Scholar 

  127. Chen M, Luo C, Zhao J, Devarajan G, Xu H (2018) Immune regulation in the aging retina. Prog Retin Eye Res 28:348–368

    Google Scholar 

  128. Rachel RA, Li T, Swaroop A (2012) Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins. Cilia 1:22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Beltran WA, Cideciyan AV, Lewin AS, Iwabe S, Khanna H, Sumaroka A, Chiodo VA, Fajardo DS, Roman AJ, Deng WT, Swider M, Aleman TS, Boye SL, Genini S, Swaroop A, Hauswirth WW, Jacobson SG, Aguirre GD (2012) Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc Natl Acad Sci USA 109:2132–2137

    Article  PubMed  PubMed Central  Google Scholar 

  130. Lheriteau E, Petit L, Weber M, Le Meur G, Deschamps JY, Libeau L, Mendes-Madeira A, Guihal C, Francois A, Guyon R, Provost N, Lemoine F, Papal S, El-Amraoui A, Colle MA, Moullier P, Rolling F (2014) Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy. Mol Ther 22:265–277

    Article  CAS  PubMed  Google Scholar 

  131. Simons DL, Boye SL, Hauswirth WW, Wu SM (2011) Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet–Biedl syndrome mouse model. Proc Natl Acad Sci USA 108:6276–6281

    Article  PubMed  PubMed Central  Google Scholar 

  132. Vandenberghe LH, Wilson JM, Gao G (2009) Tailoring the AAV vector capsid for gene therapy. Gene Ther 16:311–319

    Article  CAS  PubMed  Google Scholar 

  133. Zhang W, Li L, Su Q, Gao G, Khanna H (2018) Gene therapy using a miniCEP290 fragment delays photoreceptor degeneration in a mouse model of leber congenital amaurosis. Hum Gene Ther 29:42–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mookherjee S, Chen HY, Isgrig K, Yu W, Hiriyanna S, Levron R, Li T, Colosi P, Chien W, Swaroop A, Wu Z (2018) A CEP290 C-terminal domain complements the mutant CEP290 of Rd16 mice in trans and rescues retinal degeneration. Cell Rep 25(611–623):e6

    Google Scholar 

  135. Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, Loges NT, Bridoux AM, Pennarun G, Duriez B, Escudier E, Mitchison HM, Chodhari R, Chung EM, Morgan LC, de Iongh RU, Rutland J, Pradal U, Omran H, Amselem S, Knowles MR (2006) Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. Am J Respir Crit Care Med 174:858–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chhin B, Negre D, Merrot O, Pham J, Tourneur Y, Ressnikoff D, Jaspers M, Jorissen M, Cosset FL, Bouvagnet P (2009) Ciliary beating recovery in deficient human airway epithelial cells after lentivirus ex vivo gene therapy. PLoS Genet 5:e1000422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ostrowski LE, Yin W, Patel M, Sechelski J, Rogers T, Burns K, Grubb BR, Olsen JC (2014) Restoring ciliary function to differentiated primary ciliary dyskinesia cells with a lentiviral vector. Gene Ther 21:253–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. McIntyre JC, Davis EE, Joiner A, Williams CL, Tsai IC, Jenkins PM, McEwen DP, Zhang L, Escobado J, Thomas S, Szymanska K, Johnson CA, Beales PL, Green ED, Mullikin JC, Program NCS, Sabo A, Muzny DM, Gibbs RA, Attie-Bitach T, Yoder BK, Reed RR, Katsanis N, Martens JR (2012) Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat Med 18:1423–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Williams CL, Uytingco CR, Green WW, McIntyre JC, Ukhanov K, Zimmerman AD, Shively DT, Zhang L, Nishimura DY, Sheffield VC, Martens JR (2017) Gene therapeutic reversal of peripheral olfactory impairment in Bardet–Biedl syndrome. Mol Ther 25:904–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Boyd RF, Sledge DG, Boye SL, Boye SE, Hauswirth WW, Komaromy AM, Petersen-Jones SM, Bartoe JT (2016) Photoreceptor-targeted gene delivery using intravitreally administered AAV vectors in dogs. Gene Ther 23:223–230

    Article  CAS  PubMed  Google Scholar 

  141. Harvey AR, Kamphuis W, Eggers R, Symons NA, Blits B, Niclou S, Boer GJ, Verhaagen J (2002) Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors. Mol Cell Neurosci 21:141–157

    Article  CAS  PubMed  Google Scholar 

  142. Ruggiero A, Villa CH, Bander E, Rey DA, Bergkvist M, Batt CA, Manova-Todorova K, Deen WM, Scheinberg DA, McDevitt MR (2010) Paradoxical glomerular filtration of carbon nanotubes. Proc Natl Acad Sci USA 107:12369–12374

    Article  PubMed  PubMed Central  Google Scholar 

  143. Asico LD, Cuevas S, Ma X, Jose PA, Armando I, Konkalmatt PR (2018) Nephron segment-specific gene expression using AAV vectors. Biochem Biophys Res Commun 497:19–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Heidenreich M, Zhang F (2016) Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci 17:36–44

    Article  CAS  PubMed  Google Scholar 

  145. Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157:1262–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Haurwitz RE, Jinek M, Wiedenheft B, Zhou K, Doudna JA (2010) Sequence- and structure-specific RNA processing by a CRISPR endonuclease. Science 329:1355–1358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A, Caballero D, Harron R, Stathopoulou TR, Massey C, Shelton JM, Bassel-Duby R, Piercy RJ, Olson EN (2018) Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science 362:86–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ousterout DG, Kabadi AM, Thakore PI, Majoros WH, Reddy TE, Gersbach CA (2015) Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat Commun 6:6244

    Article  CAS  PubMed  Google Scholar 

  150. Paquet D, Kwart D, Chen A, Sproul A, Jacob S, Teo S, Olsen KM, Gregg A, Noggle S, Tessier-Lavigne M (2016) Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Nature 533:125–129

    Article  CAS  PubMed  Google Scholar 

  151. Yin H, Song CQ, Dorkin JR, Zhu LJ, Li Y, Wu Q, Park A, Yang J, Suresh S, Bizhanova A, Gupta A, Bolukbasi MF, Walsh S, Bogorad RL, Gao G, Weng Z, Dong Y, Koteliansky V, Wolfe SA, Langer R, Xue W, Anderson DG (2016) Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol 34:328–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Deng WL, Gao ML, Lei XL, Lv JN, Zhao H, He KW, Xia XX, Li LY, Chen YC, Li YP, Pan D, Xue T, Jin ZB (2018) Gene correction reverses ciliopathy and photoreceptor loss in iPSC-derived retinal organoids from retinitis pigmentosa patients. Stem Cell Rep 10:1267–1281

    Article  CAS  Google Scholar 

  153. Ruan GX, Barry E, Yu D, Lukason M, Cheng SH, Scaria A (2017) CRISPR/Cas9-mediated genome editing as a therapeutic approach for leber congenital amaurosis 10. Mol Ther 25:331–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lai M, Pifferi M, Bush A, Piras M, Michelucci A, Di Cicco M, del Grosso A, Quaranta P, Cursi C, Tantillo E, Franceschi S, Mazzanti MC, Simi P, Saggese G, Boner A, Pistello M (2016) Gene editing of DNAH11 restores normal cilia motility in primary ciliary dyskinesia. J Med Genet 53:242–249

    Article  CAS  PubMed  Google Scholar 

  155. Wu X, Scott DA, Kriz AJ, Chiu AC, Hsu PD, Dadon DB, Cheng AW, Trevino AE, Konermann S, Chen S, Jaenisch R, Zhang F, Sharp PA (2014) Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells. Nat Biotechnol 32:670–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Simhadri VL, McGill J, McMahon S, Wang J, Jiang H, Sauna ZE (2018) Prevalence of pre-existing antibodies to CRISPR-associated nuclease Cas9 in the USA population. Mol Ther Methods Clin Dev 10:105–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Jin H, Nachury MV (2009) The BBSome. Curr Biol 19:R472–R473

    Article  CAS  PubMed  Google Scholar 

  158. Kim YJ, Kim S, Jung Y, Jung E, Kwon HJ, Kim J (2018) Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes. J Clin Investig 128:3642–3648

    Article  PubMed  PubMed Central  Google Scholar 

  159. Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK, Cheng H, Scott A, Hurd RE, Sayer JA, Otto EA, Attanasio M, O’Toole JF, Jin G, Shou C, Hildebrandt F, Williams DS, Heckenlively JR, Swaroop A (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15:1847–1857

    Article  CAS  PubMed  Google Scholar 

  160. Barbelanne M, Hossain D, Chan DP, Peranen J, Tsang WY (2015) Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. Hum Mol Genet 24:2185–2200

    Article  CAS  PubMed  Google Scholar 

  161. Shimada H, Lu Q, Insinna-Kettenhofen C, Nagashima K, English MA, Semler EM, Mahgerefteh J, Cideciyan AV, Li T, Brooks BP, Gunay-Aygun M, Jacobson SG, Cogliati T, Westlake CJ, Swaroop A (2017) In vitro modeling using ciliopathy-patient-derived cells Reveals distinct cilia dysfunctions caused by CEP290 mutations. Cell Rep 20:384–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M, Huntzicker EG, Sfakianos MK, Sandoval W, Bazan JF, Kulkarni P, Garcia-Gonzalo FR, Seol AD, O’Toole JF, Held S, Reutter HM, Lane WS, Rafiq MA, Noor A, Ansar M, Devi AR, Sheffield VC, Slusarski DC, Vincent JB, Doherty DA, Hildebrandt F, Reiter JF, Jackson PK (2011) Mapping the NPHP–JBTS–MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Barbelanne M, Song J, Ahmadzai M, Tsang WY (2013) Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis. Hum Mol Genet 22:2482–2494

    Article  CAS  PubMed  Google Scholar 

  164. Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG (2010) Functional genomic screen for modulators of ciliogenesis and cilium length. Nature 464:1048–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Husson H, Moreno S, Smith LA, Smith MM, Russo RJ, Pitstick R, Sergeev M, Ledbetter SR, Bukanov NO, Lane M, Zhang K, Billot K, Carlson G, Shah J, Meijer L, Beier DR, Ibraghimov-Beskrovnaya O (2016) Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis. Hum Mol Genet 25:2245–2255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Srivastava S, Ramsbottom SA, Molinari E, Alkanderi S, Filby A, White K, Henry C, Saunier S, Miles CG, Sayer JA (2017) A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies. Hum Mol Genet 26:4657–4667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Slaats GG, Saldivar JC, Bacal J, Zeman MK, Kile AC, Hynes AM, Srivastava S, Nazmutdinova J, den Ouden K, Zagers MS, Foletto V, Verhaar MC, Miles C, Sayer JA, Cimprich KA, Giles RH (2015) DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome. J Clin Investig 125:3657–3666

    Article  PubMed  PubMed Central  Google Scholar 

  168. Fischer MD, McClements ME, Martinez-Fernandez de la Camara C, Bellingrath JS, Dauletbekov D, Ramsden SC, Hickey DG, Barnard AR, MacLaren RE (2017) Codon-optimized RPGR improves stability and efficacy of AAV8 gene therapy in two mouse models of X-linked retinitis pigmentosa. Mol Ther 25:1854–1865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Song C, Conlon TJ, Deng WT, Coleman KE, Zhu P, Plummer C, Mandapati S, Van Hoosear M, Green KB, Sonnentag P, Sharma AK, Timmers A, Robinson PM, Knop DR, Hauswirth WW, Chulay JD, Shearman MS, Ye GJ (2018) Toxicology and pharmacology of an AAV vector expressing codon-optimized RPGR in RPGR-deficient Rd9 mice. Hum Gene Ther Clin Dev 29:188–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Pawlyk BS, Smith AJ, Buch PK, Adamian M, Hong DH, Sandberg MA, Ali RR, Li T (2005) Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Investig Ophthalmol Vis Sci 46:3039–3045

    Article  Google Scholar 

  171. Bukanov NO, Moreno SE, Natoli TA, Rogers KA, Smith LA, Ledbetter SR, Oumata N, Galons H, Meijer L, Ibraghimov-Beskrovnaya O (2012) CDK inhibitors R-roscovitine and S-CR171 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. Cell Cycle 11:4040–4046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the Korean Health Industry Development Institute Grants (HI18C0013) funded by the Korean Ministry of Health and Welfare.

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Kim, Y.J., Kim, J. Therapeutic perspectives for structural and functional abnormalities of cilia. Cell. Mol. Life Sci. 76, 3695–3709 (2019). https://doi.org/10.1007/s00018-019-03158-6

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