Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas

Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS

Tuberculous Abscesses in the Head and Neck Region

Tuberculosis represents a global health challenge and is one of the leading infectious killers, with over a million people succumbing to it every year. While the disease is primarily prevalent in developing countries, where 95% of cases and deaths occur, doctors around the globe need to be able to recognize its diverse clinical manifestations in order to initiate appropriate treatment early. The granulomatous infection caused by Mycobacterium tuberculosis typically affects the lungs, but isolated abscesses in the head and neck region can be a less common presentation of the disease, potentially resulting in dysphagia, odynophagia, voice changes, neck swelling, bone erosion, and even life-threatening respiratory distress requiring tracheostomy. Here, characteristic imaging findings and potential surgical options are discussed

Human audiometric thresholds do not predict specific cellular damage in the inner ear

Introduction: As otology enters the field of gene therapy and human studies commence, the question arises whether audiograms - the current gold standard for the evaluation of hearing function - can consistently predict cellular damage within the human inner ear and thus should be used to define inclusion criteria for trials. Current assumptions rely on the analysis of small groups of human temporal bones post mortem or from psychophysical identification of cochlear "dead regions" in vivo, but a comprehensive study assessing the correlation between audiometric thresholds and cellular damage within the cochlea is lacking. Methods: A total of 131 human temporal bones from 85 adult individuals (ages 19-92 years, median 69 years) with sensorineural hearing loss due to various etiologies were analyzed. Cytocochleograms - which quantify loss of hair cells, neurons, and strial atrophy along the length of the cochlea - were compared with subjects' latest available audiometric tests prior to death (time range 5 h-22 years, median 24 months). The Greenwood function and the equivalent rectangular bandwidth were used to infer, from cytocochleograms, cochlear locations corresponding to frequencies tested in clinical audio grams. Correlation between audiometric thresholds at clinically tested frequencies and cell type-specific damage in those frequency regions was examined by calculating Spearman's correlation coefficients. Results: Similar audiometric profiles reflected widely different cellular damage in the cochlea. In our diverse group of patients, audiometric thresholds tended to be more influenced by hair cell loss than by neuronal loss or strial atrophy. Spearman's correlation coefficient across frequencies was at most 0.7 and often below 0.5, with 1.0 indicating perfect correlation. Conclusions: Audiometric thresholds do not predict specific cellular damage in the human inner ear. Our study highlights the need for better non- or minimally-invasive tools, such as cochlear endoscopy, to establish cellular-level diagnosis and thereby guide therapy and monitor response to treatment. (C) 2016 Elsevier B.V. All rights reserved

Editorial: Otologic Trauma, Pathology, and Therapy

The current Research Topic tries to highlight some of the most relevant recent advances regarding sensorineural hearing loss (SNHL). The etiology of SNHL primarily involves hereditary factors, ototoxic drugs, noise, and aging, all of which trigger two main mechanisms: damage to the organ of Corti, namely mechanosensory hair cells (HCs) and non-sensory supporting cells (SCs), and/or loss of spiral ganglion neurons (SGNs) that subsequently form the auditory nerve and hence connect the inner ear to the brain.TJ was supported by the NIH/NIDCD (K08DC019683). IV-N was supported by PID2020-115274RB-I00 from the Spanish MCIN/AEI/10.13039/501100011033 and FEDER

Secreted Factors from Human Vestibular Schwannomas Can Cause Cochlear Damage

Vestibular schwannomas (VSs) are the most common tumours of the cerebellopontine angle. Ninety-five percent of people with VS present with sensorineural hearing loss (SNHL); the mechanism of this SNHL is currently unknown. To establish the first model to study the role of VS-secreted factors in causing SNHL, murine cochlear explant cultures were treated with human tumour secretions from thirteen different unilateral, sporadic VSs of subjects demonstrating varied degrees of ipsilateral SNHL. The extent of cochlear explant damage due to secretion application roughly correlated with the subjects’ degree of SNHL. Secretions from tumours associated with most substantial SNHL resulted in most significant hair cell loss and neuronal fibre disorganization. Secretions from VSs associated with good hearing or from healthy human nerves led to either no effect or solely fibre disorganization. Our results are the first to demonstrate that secreted factors from VSs can lead to cochlear damage. Further, we identified tumour necrosis factor alpha (TNFα) as an ototoxic molecule and fibroblast growth factor 2 (FGF2) as an otoprotective molecule in VS secretions. Antibody-mediated TNFα neutralization in VS secretions partially prevented hair cell loss due to the secretions. Taken together, we have identified a new mechanism responsible for SNHL due to VSs

A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear

Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities1, 2. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector3, for transgene delivery to the mouse cochlea. Cochlear explants incubated with Anc80L65 encoding eGFP demonstrated high level transduction of inner and outer hair cells (60–100%). Injection of Anc80L65 through the round window membrane resulted in highly efficient transduction of inner and outer hair cells, a substantial improvement over conventional adeno-associated virus (AAV) vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders