Autoimmune Inner Ear Disease (AIED) is a poorly understood etiology of progressive sensorineural hearing loss that is amenable to corticosteroid therapy in approximately 60% of cases. This response is lost over time due to unknown mechanisms. For those corticosteroid resistant AIED patients, few therapeutic alternatives are effective to restore or maintain hearing. The majority of studies on AIED patients have focused on corticosteroid responsive subjects as they have been easier to identify as a cohort, and are believed to be more likely to have an inflammatory etiology mediating their sensorineural hearing loss. To date, no effective therapeutic intervention exists for corticosteroid-resistant patients with AIED. IL-1b is the quintessential cytokine that mediates the innate immune response. Expression of IL-1b dictates many of the later adaptive T-cell responses in other autoimmune and inflammatory disorders. We have preliminary evidence that several IL-1? family members are aberrantly regulated in corticosteroid non- responders with AIED, and may contribute to steroid resistance. To date, there have been limited studies on the mechanisms related to steroid resistance in this disorder. Our findings provide the rationale for IL-1 blockade with Anakinra in corticosteroid resistant (non-responders) patients with AIED as a phase I open label clinical trial to determine if use of Anakinra can improve audiometric thresholds in these patients. The R21 will permit testing the hypothesis on a small scale. If evidence of efficacy for hearing restoration with anakinra can be shown in these patients (primary milestone), we propose to validate the use of anakinra in a larger cohort of corticosteroid resistant AIED patients (R33 phase).

Public Health Relevance

Patients with immune mediated hearing loss are typically treated with corticosteroids. Of those treated, approximately 60% respond, however, that response may be lost over time. Other therapies use to date have proven largely ineffectual in improving hearing. This application proposes a phase I open label clinical trial of Anakinra for corticosteroid- resistant patients to determine if this therapy is efficacious in hearing restoration.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Exploratory/Developmental Grants Phase II (R33)
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No Study Section (in-house review) (NSS)
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Hughes, Gordon B
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Feinstein Institute for Medical Research
United States
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Vambutas, Andrea; Pathak, Shresh (2016) AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss. Laryngoscope Investig Otolaryngol 1:110-115
Pathak, Shresh; Stern, Corey; Vambutas, Andrea (2015) N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients. Immunol Res 63:236-45
Vambutas, Andrea; Lesser, Martin; Mullooly, Virginia et al. (2014) Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease. J Clin Invest 124:4115-22
Pathak, Shresh; Hatam, Lynda J; Bonagura, Vincent et al. (2013) Innate immune recognition of molds and homology to the inner ear protein, cochlin, in patients with autoimmune inner ear disease. J Clin Immunol 33:1204-15
Pathak, Shresh; Goldofsky, Elliot; Vivas, Esther X et al. (2011) IL-1? is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J Immunol 186:1870-9