Selective atonal gene delivery improves balance function in a mouse model of vestibular disease

• Published in: Gene therapy Vol. 18; no. 9; pp. 884 - 890
• Main Authors: Schlecker, C, Praetorius, M, Brough, D E, Presler, R G, Hsu, C, Plinkert, P K, Staecker, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2011; Nature Publishing Group
• Subjects: 631/378/2619/1533; 692/699; 692/700/565/201; Adenoviridae - genetics; Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Applied cell therapy and gene therapy; Balance; Basic Helix-Loop-Helix Transcription Factors - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Care and treatment; Cell Biology; Disease Models, Animal; Ear diseases; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Gene transfer; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors; Glial Fibrillary Acidic Protein - genetics; Hair cells; Hair Cells, Vestibular - physiology; Health aspects; Health. Pharmaceutical industry; Human Genetics; Humans; Industrial applications and implications. Economical aspects; Math1 protein; Medical sciences; Mice; Mice, Inbred C57BL; Nanotechnology; Nitriles; original-article; Ototoxicity; Physiological aspects; Postural Balance - genetics; Promoters; Recovery of function; Regeneration; Rodents; Sensory epithelium; Serology; Serotypes; Transcription factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Vestibular diseases; Vestibular Diseases - genetics; Vestibular Diseases - physiopathology; Vestibular system; United States; atoh1; balance; Ad28; vestibular hair cell regeneration; Hair; Animal model; Nervous system diseases; Internal ear disease; Rodentia; Regeneration; Vertebrata; Mammalia; Mouse; ENT disease; Vestibular syndrome; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.33

Loss of balance is often due to loss of vestibular hair cells. In mammals, regeneration of functional hair cells in the mature sensory epithelium is limited; therefore, loss of sensory cells can lead to debilitating balance problems. Delivery of the transcription factor atonal (atoh1) after aminoglycoside ototoxicity has previously been shown to induce the transdifferentiation of supporting cells into new hair cells and restore function. A problem with mouse aminoglycoside models is that the partial loss of hair cells seen in human disease is difficult to establish consistently. To more closely mirror human clinical balance dysfunction, we have used systemic application of 3,3′-iminodipropionitrile (IDPN), a vestibulotoxic nitrile compound known to cause vestibular hair cell loss, to induce a consistent partial loss of vestibular hair cells. To determine if balance function could be restored, we delivered atoh1 using a new adenovirus vector, based on Ad28. The Ad28 adenovector is based on a human serotype with a low seroprevalence that appears to target gene delivery to vestibular supporting cells. To further provide cell type selectivity of gene delivery, we expressed atoh1 using the supporting cell-specific glial fibrillary acid protein promoter. Delivery of this vector to IDPN-damaged vestibular organs resulted in a significant recovery of vestibular hair cells and restoration of balance, as measured by time on rotarod compared with untreated controls.