A phase I clinical trial of Anakinra for Steroid-Resistant AIED

Anakinra 治疗类固醇耐药 AIED 的 I 期临床试验

• 批准号: 8889654
• 负责人: Andrea Vambutas
• 金额: $ 0.01万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889654
• 关键词: Adrenal Cortex Hormones; Autoimmune Process; Autologous; Cells; Clinical; Clinical Trials; Cochlear implant procedure; Dexamethasone; Disease; Etiology; Family member; Hearing; IL1R2 gene; Immune; Immune response; In Vitro; Inflammatory; Interleukin-1; Length; Measurement; Mediating; Molecular Profiling; Patients; Pattern; Perilymph; Phase; Phase I Clinical Trials; Plasma; Recovery; Resistance; Safety; Sensorineural Hearing Loss; Signal Transduction; Steroid Resistance; T cell response; Testing; Therapeutic; Therapeutic Intervention; Time; anakinra; base; cohort; cytokine; hearing impairment; implantation; improved; inner ear diseases; interleukin-1 receptor type II; meetings; novel; open label; peripheral blood; prevent; receptor; response; restoration

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).

自身免疫性内耳疾病（AIED）是进行性感音神经性听力的一种鲜为人知的病因

项目成果

AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss.

• DOI: 10.1002/lio2.28
• 发表时间: 2016-10
• 期刊: LARYNGOSCOPE INVESTIGATIVE OTOLARYNGOLOGY
• 影响因子: 1.9
• 作者: Vambutas, Andrea;Pathak, Shresh
• 通讯作者: Pathak, Shresh

N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients.

• DOI: 10.1007/s12026-015-8696-3
• 发表时间: 2015-12
• 期刊: Immunologic research
• 影响因子: 4.4
• 作者: Pathak S;Stern C;Vambutas A
• 通讯作者: Vambutas A

Autoimmune inner ear disease patient-associated 28-kDa proinflammatory IL-1β fragment results from caspase-7-mediated cleavage in vitro.

自身免疫性内耳疾病患者相关的 28 kDa 促炎性 IL-1β 片段由 caspase-7 介导的体外裂解产生。

• DOI: 10.1172/jci.insight.130845
• 发表时间: 2020
• 期刊: JCI insight
• 影响因子: 8
• 作者: Pathak,Shresh;Vambutas,Andrea
• 通讯作者: Vambutas,Andrea