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Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction

  • Michelle L. HastingsEmail author
  • Timothy A. Jones
Review
  • 79 Downloads

Abstract

Antisense oligonucleotides (ASOs) have shown potential as therapeutic molecules for the treatment of inner ear dysfunction. The peripheral sensory organs responsible for both hearing and equilibrium are housed within the inner ear. Hearing loss and vestibular balance problems affect a large portion of the population and limited treatment options exist. Targeting ASOs to the inner ear as a therapeutic strategy has unique pharmacokinetic and drug delivery opportunities and challenges. Here, we review ASO technology, delivery, disease targets, and other key considerations for development of this therapeutic approach.

Key Words

Usher syndrome antisense oligonucleotides splicing sensorineural hearing loss hearing loss deafness RNA interference 

Notes

Acknowledgments

We thank Jessica Centa, Anthony Hinrich, Francine Jodelka, and Wren Michaels for the critical comments. We regret the omission of relevant content that could not be included in the interest of space.

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Supplementary material

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References

  1. 1.
    Wilson BS, Tucci DL, Merson MH, O'Donoghue GM. Global hearing health care: new findings and perspectives. Lancet. 2017;390(10111):2503–15.CrossRefGoogle Scholar
  2. 2.
    Smith RJ, Bale JF, Jr., White KR. Sensorineural hearing loss in children. Lancet. 2005;365(9462):879–90.CrossRefGoogle Scholar
  3. 3.
    Shearer AE, Hildebrand MS, Smith RJH. Hereditary Hearing Loss and Deafness Overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA)1993.Google Scholar
  4. 4.
    Van Camp G, Willems PJ, Smith RJ. Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet 1997;60(4):758–64.Google Scholar
  5. 5.
    Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, et al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med : Off J Am Coll Med Genet 2014;16(4):347–55.CrossRefGoogle Scholar
  6. 6.
    Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, et al. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet 2018;103(4):484–97.CrossRefGoogle Scholar
  7. 7.
    Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet 2016;135(4):441–50.CrossRefGoogle Scholar
  8. 8.
    Lopez C. The vestibular system: balancing more than just the body. Curr Opin Neurol 2016;29(1):74–83.CrossRefGoogle Scholar
  9. 9.
    Agrawal Y, Carey JP, Della Santina CC, Schubert MC, Minor LB. Disorders of balance and vestibular function in US adults: data from the National Health and Nutrition Examination Survey, 2001-2004. Arch Intern Med 2009;169(10):938–44.CrossRefGoogle Scholar
  10. 10.
    Ji L, Zhai S. Aging and the peripheral vestibular system. J Otolaryngol 2018;13(4):138–40.Google Scholar
  11. 11.
    Dillon CF, Gu Q, Hoffman HJ, Ko CW. Vision, hearing, balance, and sensory impairment in Americans aged 70 years and over: United States, 1999-2006. NCHS Data Brief 2010(31):1–8.Google Scholar
  12. 12.
    Agrawal Y, Pineault KG, Semenov YR. Health-related quality of life and economic burden of vestibular loss in older adults. Laryngoscope Investig Otolaryngol 2018;3(1):8–15.CrossRefGoogle Scholar
  13. 13.
    Jones SM, Jones TA. Genetics of peripheral vestibular dysfunction: lessons from mutant mouse strains. J Am Acad Audiol 2014;25(3):289–301.CrossRefGoogle Scholar
  14. 14.
    Ahmed H, Shubina-Oleinik O, Holt JR. Emerging Gene Therapies for Genetic Hearing Loss. J Assoc Res Otolaryngol: JARO 2017;18(5):649–70.CrossRefGoogle Scholar
  15. 15.
    Akil O, Oursler AE, Fan K, Lustig LR. Mouse Auditory Brainstem Response Testing. Bio Protoc. 2016;6(6).Google Scholar
  16. 16.
    Hall JW, 3rd. Development of the ear and hearing. J Perinatol 2000;20(8 Pt 2):S12–20.CrossRefGoogle Scholar
  17. 17.
    Magarinos M, Contreras J, Aburto MR, Varela-Nieto I. Early development of the vertebrate inner ear. Anat Rec (Hoboken) 2012;295(11):1775–90.CrossRefGoogle Scholar
  18. 18.
    Alagramam KN, Gopal SR, Geng R, Chen DH, Nemet I, Lee R, et al. A small molecule mitigates hearing loss in a mouse model of Usher syndrome III. Nat Chem Biol 2016;12(6):444–51.CrossRefGoogle Scholar
  19. 19.
    Du X, Cai Q, West MB, Youm I, Huang X, Li W, et al. Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs. Mol Ther : J Am Soc Gene Ther 2018;26(5):1313–26.CrossRefGoogle Scholar
  20. 20.
    Salt AN, Hirose K. Communication pathways to and from the inner ear and their contributions to drug delivery. Hear Res 2018;362:25–37.CrossRefGoogle Scholar
  21. 21.
    Glueckert R, Johnson Chacko L, Rask-Andersen H, Liu W, Handschuh S, Schrott-Fischer A. Anatomical basis of drug delivery to the inner ear. Hear Res 2018;368:10–27.CrossRefGoogle Scholar
  22. 22.
    Isgrig K, Chien WW. Posterior Semicircular Canal Approach for Inner Ear Gene Delivery in Neonatal Mouse. J Vis Exp 2018(133).Google Scholar
  23. 23.
    Yoshimura H, Shibata SB, Ranum PT, Smith RJH. Enhanced viral-mediated cochlear gene delivery in adult mice by combining canal fenestration with round window membrane inoculation. Sci Rep 2018;8(1):2980.CrossRefGoogle Scholar
  24. 24.
    Isgrig K, Chien WW. Surgical Methods for Inner Ear Gene Delivery in Neonatal Mouse. Methods Mol Biol 2019;1937:221–6.Google Scholar
  25. 25.
    Akil O, Rouse SL, Chan DK, Lustig LR. Surgical method for virally mediated gene delivery to the mouse inner ear through the round window membrane. J Vis Exp 2015(97).Google Scholar
  26. 26.
    Shibata SB, Ranum PT, Moteki H, Pan B, Goodwin AT, Goodman SS, et al. RNA Interference Prevents Autosomal-Dominant Hearing Loss. Am J Hum Genet 2016;98(6):1101–13.CrossRefGoogle Scholar
  27. 27.
    Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, et al. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol 2017;35(3):264–72.CrossRefGoogle Scholar
  28. 28.
    Salt AN, Plontke SK. Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications. Hear Res 2018;368:28–40.CrossRefGoogle Scholar
  29. 29.
    Li L, Chao T, Brant J, O'Malley B, Jr., Tsourkas A, Li D. Advances in nano-based inner ear delivery systems for the treatment of sensorineural hearing loss. Adv Drug Deliv Rev 2017;108:2–12.CrossRefGoogle Scholar
  30. 30.
    Goycoolea MV. Clinical aspects of round window membrane permeability under normal and pathological conditions. Acta Otolaryngol 2001;121(4):437–47.CrossRefGoogle Scholar
  31. 31.
    Zhu BZ, Saleh J, Isgrig KT, Cunningham LL, Chien WW. Hearing Loss after Round Window Surgery in Mice Is due to Middle Ear Effusion. Audiol Neurootol 2016;21(6):356–64.CrossRefGoogle Scholar
  32. 32.
    Guo JY, He L, Qu TF, Liu YY, Liu K, Wang GP, et al. Canalostomy As a Surgical Approach to Local Drug Delivery into the Inner Ears of Adult and Neonatal Mice. J Vis Exp 2018(135).Google Scholar
  33. 33.
    Maeda Y, Sheffield AM, Smith RJ. Therapeutic regulation of gene expression in the inner ear using RNA interference. Adv Otorhinolaryngol 2009;66:13–36.Google Scholar
  34. 34.
    Zhang W, Kim SM, Wang W, Cai C, Feng Y, Kong W, et al. Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success. Front Mol Neurosci 2018;11:221.CrossRefGoogle Scholar
  35. 35.
    Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res 2016;44(14):6549–63.CrossRefGoogle Scholar
  36. 36.
    Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol 2017;35(3):238–48.CrossRefGoogle Scholar
  37. 37.
    Bennett CF. Therapeutic Antisense Oligonucleotides Are Coming of Age. Annu Rev Med 2019;70:307–21.CrossRefGoogle Scholar
  38. 38.
    Seth PP, Tanowitz M, Bennett CF. Selective tissue targeting of synthetic nucleic acid drugs. J Clin Invest 2019.Google Scholar
  39. 39.
    Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–55.CrossRefGoogle Scholar
  40. 40.
    Lam JK, Chow MY, Zhang Y, Leung SW. siRNA Versus miRNA as Therapeutics for Gene Silencing. Mol Ther Nucleic Acids. 2015;4:e252.CrossRefGoogle Scholar
  41. 41.
    Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018;379(1):11–21.CrossRefGoogle Scholar
  42. 42.
    Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013;369(9):819–29.CrossRefGoogle Scholar
  43. 43.
    Maeda Y, Fukushima K, Nishizaki K, Smith RJ. In vitro and in vivo suppression of GJB2 expression by RNA interference. Hum Mol Genet 2005;14(12):1641–50.CrossRefGoogle Scholar
  44. 44.
    Hill K, Yuan H, Wang X, Sha SH. Noise-Induced Loss of Hair Cells and Cochlear Synaptopathy Are Mediated by the Activation of AMPK. J Neurosci 2016;36(28):7497–510.CrossRefGoogle Scholar
  45. 45.
    Xiong H, Long H, Pan S, Lai R, Wang X, Zhu Y, et al. Inhibition of Histone Methyltransferase G9a Attenuates Noise-Induced Cochlear Synaptopathy and Hearing Loss. Journal of the Association for Research in Otolaryngology : JARO. 2019.Google Scholar
  46. 46.
    Wang X, Zhu Y, Long H, Pan S, Xiong H, Fang Q, et al. Mitochondrial Calcium Transporters Mediate Sensitivity to Noise-Induced Losses of Hair Cells and Cochlear Synapses. Front Mol Neurosci 2018;11:469.CrossRefGoogle Scholar
  47. 47.
    Mukherjea D, Jajoo S, Kaur T, Sheehan KE, Ramkumar V, Rybak LP. Transtympanic administration of short interfering (si)RNA for the NOX3 isoform of NADPH oxidase protects against cisplatin-induced hearing loss in the rat. Antioxid Redox Signal 2010;13(5):589–98.CrossRefGoogle Scholar
  48. 48.
    Kaur T, Mukherjea D, Sheehan K, Jajoo S, Rybak LP, Ramkumar V. Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation. Cell Death Dis 2011;2:e180.CrossRefGoogle Scholar
  49. 49.
    Kim YJ, Kim J, Tian C, Lim HJ, Kim YS, Chung JH, et al. Prevention of cisplatin-induced ototoxicity by the inhibition of gap junctional intercellular communication in auditory cells. Cell Mol Life Sci 2014;71(19):3859–71.CrossRefGoogle Scholar
  50. 50.
    Oishi N, Chen FQ, Zheng HW, Sha SH. Intra-tympanic delivery of short interfering RNA into the adult mouse cochlea. Hear Res 2013;296:36–41.CrossRefGoogle Scholar
  51. 51.
    Yoshimura H, Shibata SB, Ranum PT, Moteki H, Smith RJH. Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness. Mol Ther : J Am Soc Gene Ther 2019.Google Scholar
  52. 52.
    Zhao Y, Wang D, Zong L, Zhao F, Guan L, Zhang P, et al. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family. PLoS One 2014;9(5):e97064.CrossRefGoogle Scholar
  53. 53.
    Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet 2002;30(3):277–84.CrossRefGoogle Scholar
  54. 54.
    Lentz JJ, Jodelka FM, Hinrich AJ, McCaffrey KE, Farris HE, Spalitta MJ, et al. Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med 2013;19(3):345–50.CrossRefGoogle Scholar
  55. 55.
    Wang L, Kempton JB, Brigande JV. Gene Therapy in Mouse Models of Deafness and Balance Dysfunction. Front Mol Neurosci 2018;11:300.CrossRefGoogle Scholar
  56. 56.
    Devare J, Gubbels S, Raphael Y. Outlook and future of inner ear therapy. Hear Res 2018;368:127–35.CrossRefGoogle Scholar
  57. 57.
    Sayyid ZN, Kim GS, Cheng AG. Molecular therapy for genetic and degenerative vestibular disorders. Curr Opin Otolaryngol Head Neck Surg 2018;26(5):307–11.Google Scholar
  58. 58.
    Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, et al. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018;553(7687):217–21.CrossRefGoogle Scholar
  59. 59.
    Du X, Li W, Gao X, West MB, Saltzman WM, Cheng CJ, et al. Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA. Hear Res 2013;304:91–110.CrossRefGoogle Scholar
  60. 60.
    Bennett CF, Baker BF, Pham N, Swayze E, Geary RS. Pharmacology of Antisense Drugs. Annu Rev Pharmacol Toxicol 2017;57:81–105.CrossRefGoogle Scholar
  61. 61.
    Ku SH, Jo SD, Lee YK, Kim K, Kim SH. Chemical and structural modifications of RNAi therapeutics. Adv Drug Deliv Rev 2016;104:16–28.CrossRefGoogle Scholar
  62. 62.
    Rigo F, Chun SJ, Norris DA, Hung G, Lee S, Matson J, et al. Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J Pharmacol Exp Ther 2014;350(1):46–55.CrossRefGoogle Scholar
  63. 63.
    Crooke ST. Molecular Mechanisms of Antisense Oligonucleotides. Nucleic acid therapeutics 2017;27(2):70–7.CrossRefGoogle Scholar
  64. 64.
    Summerton J. Morpholino antisense oligomers: the case for an RNase H-independent structural type. Biochim Biophys Acta 1999;1489(1):141–58.CrossRefGoogle Scholar
  65. 65.
    Yu RZ, Grundy JS, Geary RS. Clinical pharmacokinetics of second generation antisense oligonucleotides. Expert Opin Drug Metab Toxicol 2013;9(2):169–82.CrossRefGoogle Scholar
  66. 66.
    Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med 2017;377(18):1723–32.CrossRefGoogle Scholar
  67. 67.
    Li D, Mastaglia FL, Fletcher S, Wilton SD. Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping. Trends Pharmacol Sci 2018;39(11):982–94.CrossRefGoogle Scholar
  68. 68.
    Cerritelli SM, Crouch RJ. Ribonuclease H: the enzymes in eukaryotes. FEBS J 2009;276(6):1494–505.CrossRefGoogle Scholar
  69. 69.
    Geary RS, Baker BF, Crooke ST. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro((R))): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin Pharmacokinet 2015;54(2):133–46.CrossRefGoogle Scholar
  70. 70.
    Parham JS, Goldberg AC. Mipomersen and its use in familial hypercholesterolemia. Expert Opin Pharmacother 2018:1–5.Google Scholar
  71. 71.
    Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med 2018;379(1):22–31.CrossRefGoogle Scholar
  72. 72.
    Kimberling WJ, Hildebrand MS, Shearer AE, Jensen ML, Halder JA, Trzupek K, et al. Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children. Genet Med : Off J Am Coll Med Genet 2010;12(8):512–6.CrossRefGoogle Scholar
  73. 73.
    Mathur P, Yang J. Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta 2015;1852(3):406–20.CrossRefGoogle Scholar
  74. 74.
    El-Amraoui A, Petit C. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci 2005;118(Pt 20):4593–603.CrossRefGoogle Scholar
  75. 75.
    Reiners J, Nagel-Wolfrum K, Jurgens K, Marker T, Wolfrum U. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res 2006;83(1):97–119.CrossRefGoogle Scholar
  76. 76.
    Kremer H, van Wijk E, Marker T, Wolfrum U, Roepman R. Usher syndrome: molecular links of pathogenesis, proteins and pathways. Hum Mol Genet. 2006;15 Spec No 2:R262–70.Google Scholar
  77. 77.
    Ponnath A, Depreux, F.F., Jodelka, F.M., Rigo, F., Farris, H., Hastings, M.L., Lentz, J.J. Rescue of outer hair cells with antisense oligonucleotides in Usher mice is dependent on age of treatment. . J Assoc Res Otolaryngol provisionally accepted.Google Scholar
  78. 78.
    Vijayakumar S, Depreux FF, Jodelka FM, Lentz JJ, Rigo F, Jones TA, et al. Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide. Hum Mol Genet. 2017;doi:  https://doi.org/10.1093/hmg/ddx234.
  79. 79.
    Donaldson TN, Jennings KT, Cherep LA, McNeela AM, Depreux FF, Jodelka FM, et al. Antisense oligonucleotide therapy rescues disruptions in organization of exploratory movements associated with Usher syndrome type 1C in mice. Behav Brain Res 2018;338:76–87.CrossRefGoogle Scholar
  80. 80.
    Depreux FF, Wang L, Jiang H, Jodelka FM, Rosencrans RF, Rigo F, et al. Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse. Nucleic Acids Res 2016;44(20):9519–29.Google Scholar
  81. 81.
    Baux D, Blanchet C, Hamel C, Meunier I, Larrieu L, Faugere V, et al. Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots. Hum Mutat 2014;35(10):1179–86.CrossRefGoogle Scholar
  82. 82.
    Vache C, Besnard T, le Berre P, Garcia-Garcia G, Baux D, Larrieu L, et al. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy. Hum Mutat 2012;33(1):104–8.CrossRefGoogle Scholar
  83. 83.
    Slijkerman RW, Vache C, Dona M, Garcia-Garcia G, Claustres M, Hetterschijt L, et al. Antisense Oligonucleotide-based Splice Correction for USH2A-associated Retinal Degeneration Caused by a Frequent Deep-intronic Mutation. Mol Ther Nucleic Acids 2016;5(10):e381.CrossRefGoogle Scholar
  84. 84.
    Slijkerman R, Goloborodko A, Broekman S, de Vrieze E, Hetterschijt L, Peters T, et al. Poor Splice-Site Recognition in a Humanized Zebrafish Knockin Model for the Recurrent Deep-Intronic c.7595-2144A>G Mutation in USH2A. Zebrafish. 2018;15(6):597–609.CrossRefGoogle Scholar
  85. 85.
    Liquori A, Vache C, Baux D, Blanchet C, Hamel C, Malcolm S, et al. Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations. Hum Mutat 2016;37(2):184–93.CrossRefGoogle Scholar
  86. 86.
    Leroy BP, Aragon-Martin JA, Weston MD, Bessant DA, Willis C, Webster AR, et al. Spectrum of mutations in USH2A in British patients with Usher syndrome type II. Exp Eye Res 2001;72(5):503–9.CrossRefGoogle Scholar
  87. 87.
    Beneyto MM, Cuevas JM, Millan JM, Espinos C, Mateu E, Gonzalez-Cabo P, et al. Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2). Ophthalmic Genet 2000;21(2):123–8.CrossRefGoogle Scholar
  88. 88.
    Yan D, Ouyang X, Patterson DM, Du LL, Jacobson SG, Liu XZ. Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II. J Hum Genet 2009;54(12):732–8.CrossRefGoogle Scholar
  89. 89.
    Aller E, Jaijo T, Beneyto M, Najera C, Oltra S, Ayuso C, et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet 2006;43(11):e55.CrossRefGoogle Scholar
  90. 90.
    Hartel BP, Lofgren M, Huygen PL, Guchelaar I, Lo ANKN, Sadeghi AM, et al. A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa. Hear Res 2016;339:60–8.CrossRefGoogle Scholar
  91. 91.
    Khan AO, Becirovic E, Betz C, Neuhaus C, Altmuller J, Maria Riedmayr L, et al. A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula. Sci Rep 2017;7(1):1411.CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Center for Genetic Diseases, Chicago Medical SchoolRosalind Franklin University of Science and MedicineNorth ChicagoUSA
  2. 2.Department of Special Education and Communication DisordersUniversity of Nebraska-LincolnLincolnUSA

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