Kim Baker

Vestibular hair cell regeneration and restoration of balance function induced by math1 gene transfer.

Hypothesis: Delivery of math1 using an adenovector (Admath1.11D) results in vestibular hair cell regeneration and recovery of balance function in ototoxin-treated adult mice. Background: Loss of peripheral vestibular function is associated with disease processes such as vestibular neuronitis, aminoglycoside ototoxicity, and aging. Loss of vestibular hair cells is one of the mechanisms underlying balance dysfunction in all of these disorders. Currently, recovery from these diseases relies on central vestibular compensation rather than on local tissue recovery. Overexpression of the mammalian atonal homologue math1 has been demonstrated to induce generation of hair cells in neonatal organ of Corti cultures and in the guinea pig cochlea in vivo and could thus provide an approach to local tissue recovery. Methods: Admath1.11D was applied to cultures of aminoglycoside-treated macular organs or in vivo in a mouse aminoglycoside ototoxicity model. Outcome measures included histologic examination, immunohistochemistry, swim testing, and evaluation of the horizontal vestibulo-ocular reflex. Results: Delivery of math1 resulted in the generation of vestibular hair cells in vitro after aminoglycoside-mediated loss of hair cells. Math1-treated mice showed recovery of the vestibular neuroepithelium within 8 weeks after Admath1.11D treatment. Assessment of animals after vector infusion demonstrated a recovery of vestibular function compared with aminoglycoside-only-treated mice. Conclusion: Molecular replacement of math1 may provide a therapeutic means of restoring vestibular function related to vestibular hair cell loss.

Hearing preservation after inner ear gene therapy: The effect of vector and surgical approach

Over seventy studies have examined the potential of gene therapy in the inner ear. For the most part, they have focused on adenoviral vectors and delivery into the cochlea. Most studies have emphasized looking at the expression of marker genes driven by a CMV promoter and have used first-generation adenoviral constructs. E1/E3/E4 deleted adenoviral vectors carrying the green fluorescent protein (GFP) gene were injected into the round window, the basal turn of the cochlea (via a cochleostomy) or into the superior semicircular canal. Hearing was then tested 24 h after viral gene transfer. Large vector titers in small volumes of fluid were well tolerated with the round window approach resulting in complete hearing preservation with transfer of GFP to hair cells and spiral ganglion cells. Injection of comparable doses of vector into a basal turn cochleostomy resulted in high-frequency hearing loss. Addition of a pancaspase inhibitor protected hearing when larger volumes of fluid were administered to the inner ear.

Repair of the Vestibular System via Adenovector Delivery of Atoh1: A Potential Treatment for Balance Disorders

Loss of auditory and vestibular hair cells is a common cause of hearing loss and balance disorders. A variety of strategies have been proposed to restore function to damaged inner ear neuroepithelium. Delivery of the atonal homolog, atoh1, has been demonstrated to induce recovery of auditory and vestibular hair cells using a variety of delivery methods and model systems. We have developed a mouse model of vestibular aminoglycoside ototoxicity and demonstrated that delivery of an advanced generation adenovector that expresses atoh1 results in the regeneration of vestibular hair cells. Additionally, mice treated with atoh1 recover balance function. Currently vestibular diseases have few treatment options and several lines of evidence suggest that regeneration of hair cells may be more easily accomplished in the vestibular system. Development of atoh1-based gene therapy for vestibular hair cell loss may provide an initial opportunity for developing gene therapy for inner ear disease.

A Case of Atrophic Rhinitis Caused by Klebsiella ozaenae

Objective: To educate clinicians on the presentation and management of this uncommon pathogen as it pertains to atrophic rhinitis and to review the role of autoimmune tendencies in the development of ozena in this patient with nasal infection by Klebsiella ozaenae. Method: This case report describes a 17-year-old Somalian female with ozena (atrophic rhinitis). She presented to our tertiary care center in Kansas City, Missouri, in November 2011 with classic symptoms of atrophic rhinitis and was diagnosed based on a positive surgical culture of K ozanae. She was noted to have bilateral middle turbinate destruction preoperatively and has been treated thus far with serial surgical debridements, topical nasal rinses and an oral fluoroquinolone. We are measuring cure of her disease with multiple parameters including improved nasal obstruction (symptomatic), endoscopic documentation of resolution of rhinitis, and pathologic/microbiologic confirmation of cure. Results: Our patient experienced temporary relief of her symptoms after endoscopic debridement. Recurrence of her symptoms was delayed by topical nasal rinses and steroids. A prolonged course of therapy with an oral fluoroquinolone augmented by serial nasal debridements was necessary to obtain resolution of her disease. Conclusion: Management of atrophic rhinitis in the setting of K ozaenae infection is a multidisciplinary approach between surgical specialists and infectious disease specialists. Autoimmune factors may play a role in development and severity of this disease.

541. Mechanisms of adenovirus vector gene delivery to the inner ear|[ast]|

Top of pageAbstract Gene delivery to the inner ear has the potential to treat hearing loss and balance disorders. A number of studies have shown that adenovirus vectors can transduce sensory and non-sensensory cells within the inner ear. In addition, the expression of growth factors and regulatory genes has been shown to have biological effects. As more candidate therapeutic genes are being discovered, further understanding of the mechanisms involved in adenoviral vector transduction of the inner ear is needed. Multiply deficient and targeted adenovirus vectors have the potential to enhance safety and efficacy of a gene delivery candidate to treat hearing and balance disorders. The advantages that multiply deficient adenoviral vectors deleted of E1A, E1B, E3 and E4 for gene delivery to the inner ear have been shown and the ability of these vectors with modified capsids to specifically transduce the inner ear will be discussed.

516. Vestibular Hair Cell Regeneration and Re-Establishment of Balance Function Induced by Math1 Gene Delivery

Over expression of math1 has been demonstrated to induce generation of hair cells in the cochlea in neonatal tissue culture models of the organ of Corti and math 1 generation of hair cells has recently been shown in vivo. We have examined an in vitro organtypic culture model as well as unilateral acute and bilateral chronic models of aminoglycoside vestibular injury. Delivery of Math1 using an adenovector (Ad) resulted in the generation of hair cells in adult mouse utriclular and saccular cultures. Mice treated acutely or chronically with aminoglycosides showed recovery of a significant portion of the vestibular neuroepithelium after AdMath1.11D was infused into the inner ear. Interestingly there was no recovery of hair cells noted within the cochlea in these mouse models and no hair cells noted outside of the vestibular neuroepithelium. Assessment of animals 2 months after vector infusion demonstrated a recovery of swim times compared to non-vector treated controls, demonstrating recovery of vestibular function after Math1 gene delivery.