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There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polß+/-. The 3xTgAD/Polß+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polß+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.
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Usher syndrome is the most common cause of deafness-blindness in the world. Usher syndrome type 1B (USH1B) is associated with mutations in MYO7A. Patients with USH1B experience deafness, blindness, and vestibular dysfunction. In this study, we applied adeno-associated virus (AAV)-mediated gene therapy to the shaker-1 (Myo7a4626SB/4626SB) mouse, a model of USH1B. The shaker-1 mouse has a nonsense mutation in Myo7a, is profoundly deaf throughout life, and has significant vestibular dysfunction. Because of the â¼6.7-kb size of the MYO7A cDNA, a dual-AAV approach was used for gene delivery, which involves splitting human MYO7A cDNA into 5' and 3' halves and cloning them into two separate AAV8(Y733F) vectors. When MYO7A cDNA was delivered to shaker-1 inner ears using the dual-AAV approach, cochlear hair cell survival was improved. However, stereocilium organization and auditory function were not improved. In contrast, in the vestibular system, dual-AAV-mediated MYO7A delivery significantly rescued hair cell stereocilium morphology and improved vestibular function, as reflected in a reduction of circling behavior and improved vestibular sensory-evoked potential (VsEP) thresholds. Our data indicate that dual-AAV-mediated MYO7A expression improves vestibular function in shaker-1 mice and supports further development of this approach for the treatment of disabling dizziness from vestibular dysfunction in USH1B patients.
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Hearing loss is a common disorder affecting nearly 20% of the world's population. Recently, studies have shown that inner ear gene therapy can improve auditory function in several mouse models of hereditary hearing loss. In most of these studies, the underlying mutations affect only a small number of cell types of the inner ear (e.g., sensory hair cells). Here, we applied inner ear gene therapy to the Ildr1Gt(D178D03)Wrst (Ildr1w-/-) mouse, a model of human DFNB42, non-syndromic autosomal recessive hereditary hearing loss associated with ILDR1 variants. ILDR1 is an integral protein of the tricellular tight junction complex and is expressed by diverse inner ear cell types in the organ of Corti and the cochlear lateral wall. We simultaneously applied two synthetic adeno-associated viruses (AAVs) with different tropism to deliver Ildr1 cDNA to the Ildr1w-/- mouse inner ear: one targeting the organ of Corti (AAV2.7m8) and the other targeting the cochlear lateral wall (AAV8BP2). We showed that combined AAV2.7m8/AAV8BP2 gene therapy improves cochlear structural integrity and auditory function in Ildr1w-/- mice.
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Sordera , Pérdida Auditiva , Humanos , Animales , Ratones , Receptores de Superficie Celular/genética , Sordera/genética , Sordera/terapia , Modelos Animales de Enfermedad , Terapia GenéticaRESUMEN
Efferent brain-stem neurons release acetylcholine to desensitize cochlear hair cells and can protect the inner ear from acoustic trauma. That protection is absent from knockout mice lacking efferent inhibition and is stronger in mice with a gain-of-function point mutation of the hair cell-specific nicotinic acetylcholine receptor. The present work uses viral transduction of gain-of-function receptors to restore acoustic prophylaxis to the knockout mice. Widespread postsynaptic expression of the transgene was visualized in excised tissue with a fluorophore-conjugated peptide toxin that binds selectively to hair cell acetylcholine receptors. Viral transduction into efferent knockout mice reduced the temporary hearing loss measured 1 day post acoustic trauma. The acoustic evoked-response waveform (auditory brain-stem response) recovered more rapidly in treated mice than in control mice. Thus, both cochlear amplification by outer hair cells (threshold shift) and afferent signaling (evoked-response amplitude) in knockout mice were protected by viral transduction of hair cell acetylcholine receptors. Gene therapy to strengthen efferent cochlear feedback could be complementary to existing and future therapies to prevent hearing loss, including ear coverings, hearing aids, single-gene repair, or small-molecule therapies.
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Adeno-associated virus (AAV)-mediated inner ear gene therapy is a promising treatment option for hearing loss and dizziness. Several studies have shown that AAV-mediated inner ear gene therapy can be applied to various mouse models of hereditary hearing loss to improve their auditory function. Despite the increase in AAV-based animal and clinical studies aiming to rescue auditory and vestibular functions, little is currently known about the host immune responses to AAV in the mammalian inner ear. It has been reported that the host immune response plays an important role in the safety and efficacy of viral-mediated gene therapy. Therefore, in order for AAV-mediated gene therapy to be successfully and safely translated into patients with hearing loss and dizziness, a better understanding of the host immune responses to AAV in the inner ear is critical. In this review, we summarize the current knowledge on host immune responses to AAV-mediated gene therapy in the mammalian inner ear and other organ systems. We also outline the areas of research that are critical for ensuring the safety and efficacy of AAV-mediated inner ear gene therapy in future clinical and translational studies.
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Oído Interno , Pérdida Auditiva , Animales , Ratones , Dependovirus/genética , Técnicas de Transferencia de Gen , Mareo/terapia , Vectores Genéticos , Terapia Genética , Pérdida Auditiva/genética , Mamíferos/genéticaRESUMEN
Inner ear gene therapy using adeno-associated viruses (AAVs) has been successfully applied to several mouse models of hereditary hearing loss to improve their auditory function. While most inner ear gene therapy studies have focused on the mechanosensory hair cells and supporting cells in the organ of Corti, the cochlear lateral wall and the endolymphatic sac have not garnered much attention. The cochlear lateral wall and the endolymphatic sac play critical roles in inner ear ionic and fluid homeostasis. Mutations in genes expressed in the cochlear lateral wall and the endolymphatic sac are present in a large percentage of patients with hereditary hearing loss. In this study, we examine the transduction patterns and efficiencies of conventional (AAV2 and AAV8) and synthetic (AAV2.7m8, AAV8BP2, and Anc80L65) AAVs in the mouse inner ear. We found that AAV8BP2 and AAV8 are capable of transducing the marginal cells and intermediate cells in the stria vascularis. These two AAVs can also transduce the epithelial cells of the endolymphatic sac. Our data suggest that AAV8BP2 and AAV8 are highly useful viral vectors for gene therapy studies targeting the cochlear lateral wall and the endolymphatic sac.
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IMPORTANCE: Emerging reports of sudden sensorineural hearing loss (SSNHL) after COVID-19 vaccination within the otolaryngological community and the public have raised concern about a possible association between COVID-19 vaccination and the development of SSNHL. OBJECTIVE: To examine the potential association between COVID-19 vaccination and SSNHL. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study and case series involved an up-to-date population-based analysis of 555 incident reports of probable SSNHL in the Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System (VAERS) over the first 7 months of the US vaccination campaign (December 14, 2020, through July 16, 2021). In addition, data from a multi-institutional retrospective case series of 21 patients who developed SSNHL after COVID-19 vaccination were analyzed. The study included all adults experiencing SSNHL within 3 weeks of COVID-19 vaccination who submitted reports to VAERS and consecutive adult patients presenting to 2 tertiary care centers and 1 community practice in the US who were diagnosed with SSNHL within 3 weeks of COVID-19 vaccination. EXPOSURES: Receipt of a COVID-19 vaccine produced by any of the 3 vaccine manufacturers (Pfizer-BioNTech, Moderna, or Janssen/Johnson & Johnson) used in the US. MAIN OUTCOMES AND MEASURES: Incidence of reports of SSNHL after COVID-19 vaccination recorded in VAERS and clinical characteristics of adult patients presenting with SSNHL after COVID-19 vaccination. RESULTS: A total of 555 incident reports in VAERS (mean patient age, 54 years [range, 15-93 years]; 305 women [55.0%]; data on race and ethnicity not available in VAERS) met the definition of probable SSNHL (mean time to onset, 6 days [range, 0-21 days]) over the period investigated, representing an annualized incidence estimate of 0.6 to 28.0 cases of SSNHL per 100â¯000 people per year. The rate of incident reports of SSNHL was similar across all 3 vaccine manufacturers (0.16 cases per 100â¯000 doses for both Pfizer-BioNTech and Moderna vaccines, and 0.22 cases per 100 000 doses for Janssen/Johnson & Johnson vaccine). The case series included 21 patients (mean age, 61 years [range, 23-92 years]; 13 women [61.9%]) with SSNHL, with a mean time to onset of 6 days (range, 0-15 days). Patients were heterogeneous with respect to clinical and demographic characteristics. Preexisting autoimmune disease was present in 6 patients (28.6%). Of the 14 patients with posttreatment audiometric data, 8 (57.1%) experienced improvement after receiving treatment. One patient experienced SSNHL 14 days after receiving each dose of the Pfizer-BioNTech vaccine. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, findings from an updated analysis of VAERS data and a case series of patients who experienced SSNHL after COVID-19 vaccination did not suggest an association between COVID-19 vaccination and an increased incidence of hearing loss compared with the expected incidence in the general population.
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COVID-19 , Pérdida Auditiva Sensorineural , Pérdida Auditiva Súbita , Vacunas , Adulto , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Estudios Transversales , Femenino , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Súbita/epidemiología , Pérdida Auditiva Súbita/etiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Vacunación/efectos adversosRESUMEN
Among the various cochlear implant systems approved by the Food and Drug Administration, current labeling for pediatric usage encompasses (1) bilateral profound bilateral sensorineural hearing loss in children aged 9 to 24 months and bilateral severe to profound sensorineural hearing loss in children older than 2 years; (2) use of appropriately fitted hearing aids for 3 months (this can be waived if there is evidence of ossification); and (3) demonstration of limited progress with auditory, speech, and language development. Pediatric guidelines require children to have significantly worse speech understanding before qualifying for cochlear implantation. The early years of life have been shown to be critical for speech and language development, and auditory deprivation is especially detrimental during this crucial time.Level of evidence: 2.
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Implantación Coclear , Implantes Cocleares , Pérdida Auditiva Sensorineural , Percepción del Habla , Niño , Preescolar , Pérdida Auditiva Bilateral , Pérdida Auditiva Sensorineural/rehabilitación , Pérdida Auditiva Sensorineural/cirugía , Humanos , Derivación y Consulta , Resultado del TratamientoRESUMEN
Hearing loss is a common disability affecting the world's population today. While several studies have shown that inner ear gene therapy can be successfully applied to mouse models of hereditary hearing loss to improve hearing, most of these studies rely on inner ear gene delivery in the neonatal age, when mouse inner ear has not fully developed. However, the human inner ear is fully developed at birth. Therefore, in order for inner ear gene therapy to be successfully applied in patients with hearing loss, one must demonstrate that gene delivery can be safely and reliably performed in the mature mammalian inner ear. In this study, we examine the steps involved in posterior semicircular canal gene delivery in the adult mouse inner ear. We find that the duration of perilymphatic leakage and injection rate have a significant effect on the post-surgical hearing outcome. Our results show that although AAV2.7m8 has a lower hair cell transduction rate in adult mice compared to neonatal mice at equivalent viral load, AAV2.7m8 is capable of transducing the adult mouse inner and outer hair cells with high efficiency in a dose-dependent manner.
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Dependovirus/metabolismo , Terapia Genética/métodos , Células Ciliadas Auditivas/metabolismo , Canales Semicirculares/cirugía , Animales , Dependovirus/genética , Técnicas de Transferencia de Gen , Terapia Genética/efectos adversos , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Pérdida Auditiva , Ratones Endogámicos CBA , PerilinfaAsunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Vacunas contra la COVID-19/efectos adversos , Pérdida Auditiva Súbita/inducido químicamente , Centers for Disease Control and Prevention, U.S. , Femenino , Pérdida Auditiva Súbita/epidemiología , Humanos , Incidencia , Masculino , Maryland/epidemiología , Estados Unidos/epidemiologíaRESUMEN
HYPOTHESIS: Three-dimensional (3D) printed temporal bones are comparable to cadaveric temporal bones as a training tool for otologic surgery. BACKGROUND: Cadaveric temporal bone dissection is an integral part of otology surgical training. Unfortunately, availability of cadaveric temporal bones is becoming much more limited and concern regarding chemical and biological risks persist. In this study, we examine the validity of 3D-printed temporal bone model as an alternative training tool for otologic surgery. METHODS: Seventeen otolaryngology trainees participated in the study. They were asked to complete a series of otologic procedures using 3D-printed temporal bones. A semi-structured questionnaire was used to evaluate their dissection experience on the 3D-printed temporal bones. RESULTS: Participants found that the 3D-printed temporal bones were anatomically realistic compared to cadaveric temporal bones. They found that the 3D-printed temporal bones were useful as a surgical training tool in general and also for specific otologic procedures. Overall, participants were enthusiastic about incorporation of 3D-printed temporal bones in temporal bone dissection training courses and would recommend them to other trainees. CONCLUSION: 3D-printed temporal bone model is a viable alternative to human cadaveric temporal bones as a teaching tool for otologic surgery.
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BACKGROUND: Case-control studies from the early 2000s demonstrated that human papillomavirus-related oropharyngeal cancer (HPV-OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV-OPC. METHODS: HPV-OPC patients and frequency-matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi-square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression. RESULTS: A total of 163 HPV-OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV-OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8-6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1-3.2]) and oral sex intensity (>5 sex-years: aOR, 2.8 [95% CI, 1.1-7.5]) remained associated with significantly increased odds of HPV-OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1-2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1-2.4]) was associated with HPV-OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122-670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70-378]) was associated with increased odds of HPV-OPC. CONCLUSION: Number of oral sex partners remains a strong risk factor for HPV-OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV-OPC.
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Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Conducta Sexual , Parejas Sexuales , Adolescente , Adulto , Distribución por Edad , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Relaciones Extramatrimoniales , Femenino , Papillomavirus Humano 16/inmunología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Proteínas Oncogénicas Virales/análisis , Neoplasias Orofaríngeas/epidemiología , Proteínas Represoras/análisis , Riesgo , Factores de Riesgo , Conducta Sexual/estadística & datos numéricos , Fumar/efectos adversos , Factores Socioeconómicos , Factores de Tiempo , Estados Unidos/epidemiología , Sexo Inseguro , Adulto JovenRESUMEN
Approximately 3 in 1000 children in the US under 4 years of age are affected by hearing loss. Currently, cochlear implants represent the only line of treatment for patients with severe to profound hearing loss, and there are no targeted drug or biological based therapies available. Gene replacement is a promising therapeutic approach for hereditary hearing loss, where viral vectors are used to deliver functional cDNA to "replace" defective genes in dysfunctional cells in the inner ear. Proof-of-concept studies have successfully used this approach to improve auditory function in mouse models of hereditary hearing loss, and human clinical trials are on the immediate horizon. The success of this method is ultimately determined by the underlying biology of the defective gene and design of the treatment strategy, relying on intervention before degeneration of the sensory structures occurs. A challenge will be the delivery of a corrective gene to the proper target within the therapeutic window of opportunity, which may be unique for each specific defective gene. Although rescue of pre-lingual forms of recessive deafness have been explored in animal models thus far, future identification of genes with post-lingual onset that are amenable to gene replacement holds even greater promise for treatment, since the therapeutic window is likely open for a much longer period of time. This review summarizes the current state of adeno-associated virus (AAV) gene replacement therapy for recessive hereditary hearing loss and discusses potential challenges and opportunities for translating inner ear gene replacement therapy for patients with hereditary hearing loss.
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Dependovirus , Oído Interno , Animales , Sordera/terapia , Dependovirus/genética , Terapia Genética , Vectores Genéticos , Pérdida Auditiva/genética , Pérdida Auditiva/terapia , Pérdida Auditiva Sensorineural , Humanos , Enfermedades del Laberinto/genética , Enfermedades del Laberinto/terapiaRESUMEN
BACKGROUND: Transverse or sigmoid sinus thrombosis occurs in 4% to 11% of patients following posterior fossa surgery. Anticoagulation has been the mainstay treatment, mostly based on extrapolation from the literature on spontaneous sinus thrombosis. OBJECTIVE: To analyze the rate and associated complications of postoperative transverse/sigmoid sinus thrombosis for patients undergoing posterior fossa tumor resection. In this series, no antithrombotic therapy was initiated, and no postoperative treatment alterations were made following thrombosis diagnosis. METHODS: Prospectively accrued cases from a single surgeon operating at a single academic center were retrospectively reviewed to determine the natural history of untreated transverse/sigmoid sinus thrombosis following posterior fossa surgery. Inclusion criteria were patients 18 yr or older undergoing resection of a posterior fossa tumor. A total of 538 patients were analyzed. RESULTS: In all 26 out of 538 (4.8%) patients were diagnosed with transverse/sigmoid sinus thrombosis on routine postoperative imaging. Early postoperative complication rate was 38% in the sinus thrombosis group, as compared to 15% in the no-thrombosis group (P = .02). A significantly higher rate of pseudomeningocele, dysphagia requiring gastrostomy, and cerebellar stroke signs were noted in patients with postoperative sinus thrombosis. However, only 3 of the 26 patients (12%) with postoperative sinus occlusion suffered prolonged central nervous system complications. CONCLUSION: Transverse/sigmoid sinus thrombosis following suboccipital craniectomy results in a higher rate of early complications; however, most of these complications resolve without anticoagulation. It may be reasonable, therefore, to manage these patients conservatively in order to avoid the risks associated with anticoagulation in the perioperative period.
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Senos Craneales , Trombosis de los Senos Intracraneales , Senos Craneales/diagnóstico por imagen , Senos Craneales/cirugía , Craneotomía , Humanos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/epidemiología , Trombosis de los Senos Intracraneales/etiologíaRESUMEN
BACKGROUND: Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors. METHODS: This was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles. RESULTS: Subjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles. CONCLUSIONS: CEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.
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Bocio Nodular/genética , Haplotipos , Pérdida Auditiva Sensorineural/genética , Mutación , Fenotipo , Transportadores de Sulfato/genética , Acueducto Vestibular/anomalías , Acueducto Vestibular/patología , Adolescente , Adulto , Alelos , Audiometría , Niño , Preescolar , Cromosomas Humanos Par 7/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Audición/genética , Pérdida Auditiva/genética , Heterocigoto , Homocigoto , Humanos , Masculino , Estudios Prospectivos , Sitios de Empalme de ARN , Glándula Tiroides , Adulto JovenRESUMEN
Inner ear gene therapy offers great potential as a treatment for hearing loss and dizziness. The surgical method used to deliver gene therapy into the inner ear is a critical step in determining the success of inner ear gene therapy. Here we describe two commonly used surgical methods for gene delivery in neonatal mouse inner ear: the round window approach and the posterior semicircular canal approach. Both of these approaches are effective at delivering gene therapy to the neonatal mouse inner ear.
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Vectores Genéticos/administración & dosificación , Ventana Redonda/cirugía , Canales Semicirculares/cirugía , Animales , Animales Recién Nacidos , Oído Interno/cirugía , Técnicas de Transferencia de Gen , Terapia Genética , Ratones , Procedimientos Quirúrgicos OperativosRESUMEN
The incidence of human papillomavirus (HPV)-associated head and neck cancers is rising, particularly among men. Whether observed epidemiological differences in sex are explained by differences in sexual exposure and/or by immune response is unclear. In this cross-sectional, multi-institutional study, seroprevalence of antibodies to HPV L1 capsid antigen was compared by patient characteristics among 374 adult patients without cancer. A significantly higher seroprevalence was observed among women compared with men for HPV16 (OR = 2.96, 95% CI = 1.21-7.21) and HPV18 (OR = 2.84, 95% CI = 1.06-7.60) L1 antibodies. This difference persisted for HPV16 after controlling for lifetime and recent sexual behavior. After controlling for sex, HPV16 and HPV18 L1 seroprevalence was also significantly associated with higher number of lifetime (HPV16 OR = 1.05, 95% CI = 1.01-1.08; HPV18 OR = 1.04, 95% CI = 1.01-1.08) and recent (HPV16 OR = 1.54, 95% CI = 1.15-2.07; HPV18 OR = 1.40, 95% CI = 1.07-1.82) oral but not vaginal sexual partners. These findings potentially suggest a more robust immune response to HPV16/18 among women compared with men that may not be explained by differences in number of sexual partners, and thereby presumably HPV exposure. The independent association of HPV16/18 L1 seroprevalence with higher number of oral sexual partners suggests a possible role for site of mucosal exposure in the HPV immune response.
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Anticuerpos Antivirales/sangre , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Infecciones por Papillomavirus/inmunología , Factores Sexuales , Anciano , Anticuerpos Antivirales/inmunología , Estudios Transversales , ADN Viral/análisis , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Papillomaviridae , Infecciones por Papillomavirus/epidemiología , Estudios Seroepidemiológicos , Conducta SexualRESUMEN
Adeno-associated virus (AAV) has been successfully used to deliver gene therapy to improve auditory function in mouse models of hereditary hearing loss. Many forms of hereditary hearing loss have mutations which affect the cochlear hair cells, the mechanosensory cells which allow for sound detection and processing. While most conventional AAVs infect inner hair cells (IHCs) with various efficiencies, they infect outer hair cells (OHCs) and supporting cells at lower levels in the cochlea. Here we examine the infection patterns of two synthetic AAVs (AAV2.7m8 and AAV8BP2) in the mouse inner ear. AAV2.7m8 infects both IHCs and OHCs with high efficiency. In addition, AAV2.7m8 infects inner pillar cells and inner phalangeal cells with high efficiency. Our results suggest that AAV2.7m8 is an excellent viral vector for inner ear gene therapy targeting cochlear hair cells and supporting cells, and it will likely greatly expand the potential applications for inner ear gene therapy.
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Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Pérdida Auditiva Sensorineural/terapia , Miosinas/genética , Animales , Animales Recién Nacidos , Dependovirus/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Genes Reporteros , Vectores Genéticos/química , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células Ciliadas Auditivas Internas/patología , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patología , Audición/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/patología , Ratones , Miosina VIIa , Miosinas/metabolismoRESUMEN
Mutations in CEP290 cause ciliogenesis defects, leading to diverse clinical phenotypes, including Leber congenital amaurosis (LCA). Gene therapy for CEP290-associated diseases is hindered by the 7.4 kb CEP290 coding sequence, which is difficult to deliver in vivo. The multi-domain structure of the CEP290 protein suggests that a specific CEP290 domain may complement disease phenotypes. Thus, we constructed AAV vectors with overlapping CEP290 regions and evaluated their impact on photoreceptor degeneration in Cep290rd16/rd16 and Cep290rd16/rd16;Nrl-/- mice, two models of CEP290-LCA. One CEP290 fragment (the C-terminal 989 residues, including the domain deleted in mutant mice) reconstituted CEP290 function and resulted in cone preservation and delayed rod death. The CEP290 C-terminal domain also improved cilia phenotypes in mouse embryonic fibroblasts and iPSC-derived retinal organoids carrying the Cep290rd16 mutation. Our study strongly argues for in trans complementation of CEP290 mutations by a cognate fragment and suggests therapeutic avenues.