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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33DC011827-03
Application #
8518175
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hughes, Gordon B
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$473,810
Indirect Cost
$192,570
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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