Cochlear Gene Therapy

Ak, Lalwani; An, Mhatre

doi:10.1159/000059106

Cited by 9 publications

(7 citation statements)

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“…Each vector has its own profile of infectivity, tropism for the various cell types of the inner ear, host immune response, toxicity, duration and stability of infectivity, integration into the host genome and gene capacity, all of which must be taken into consideration for suitable vector selection and design. 25,42,43 …”

Section: Cell Viability and Availabilitymentioning

confidence: 99%

An in vitro model system to study gene therapy in the human inner ear

et al. 2007

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The confined fluid-filled labyrinth of the human inner ear presents an opportunity for introduction of gene therapy reagents designed to treat hearing and balance dysfunction. Here we present a novel model system derived from the sensory epithelia of human vestibular organs and show that the tissue can survive up to 5 days in vitro. We generated organotypic cultures from 26 human sensory epithelia excised at the time of labyrinthectomy for intractable Meniere's disease or vestibular schwannoma. We applied multiply deleted adenoviral vectors at titers between 10 5 and 10 8 viral particles/ml directly to the cultures for 4-24 h and examined the tissue 12-96 h post-transfection. We noted robust expression of the exogenous transgene, green fluorescent protein (GFP), in hair cells and supporting cells suggesting both were targets of adenoviral transfection. We also transfected cultures with a vector that carried the genes for GFP and KCNQ4, a potassium channel subunit that causes dominant-progressive hearing loss when mutated. We noted a positive correlation between GFP fluorescence and KCNQ4 immunolocalization. We conclude that our in vitro model system presents a novel and effective experimental paradigm for evaluation of gene therapy reagents designed to restore cellular function in patients who suffer from inner ear disorders.

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Section: Cell Viability and Availabilitymentioning

confidence: 99%

An in vitro model system to study gene therapy in the human inner ear

et al. 2007

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“…Replication-deficient adenoviral vectors based on human serotype 5 have been shown to transduce the mammalian inner ear efficiently both in vitro 1,2 and in vivo. [3][4][5] In vivo, some studies have shown that the most efficient transduction is seen in mesothelial cells lining the perilymphatic fluids, whereas the sensory hair cells of the organ of Corti and the spiral ganglion neurons are not transduced. 6,7 However, other studies have demonstrated that adenovirus vectors can indeed transduce sensory hair cells in the organ of Corti.…”

Section: Introductionmentioning

confidence: 99%

Coxsackie adenovirus receptor and ανβ3/ανβ5 integrins in adenovirus gene transfer of rat cochlea

et al. 2006

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This study was designed to determine whether Coxsackie adenovirus receptor (CAR) and anb3/anb5 integrin co-receptors are involved in adenovirus gene transfer in the rat cochlea. We find that CAR and integrin co-receptors are expressed in every cell subtype transduced by the adenoviral vector Ad5 DE1-E3/cytomegalovirus/green fluorescent protein (GFP) on cochlear slices in vitro. The spiral ganglion neurons, which do not express CAR, were not transduced by the virus. Blocking these receptors by monoclonal antibodies decreased transgene expression, whereas disrupting tight junctions with ethylenediaminetetraacetic acid led to an increased transgene expression. However, sensory hair cells and strial cells also expressing CAR and an integrins were not transduced by the vector.GFP expression was also studied in vivo. Perilymphatic perfusion of adenovirus in vivo did not affect hearing and only cells lining the perilymphatic spaces were transduced. Endolymphatic perfusion resulted in low-frequency hearing loss and although some cells of the organ of Corti were efficiently transduced, the sensory and the strial cells were not. Transduced sensory and strial cells were occasionally observed in cochleas after single shot of adenovirus. Pretreatment with anti-CAR and anti-an antibodies decreases GFP expression in vivo, suggesting that the CAR/an integrin pathway is involved in adenovirus transduction in the cochlea.

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“…To maintain the expression of these chains, which used to be unknown to the host, it requires immunosuppression and it is discussed what would be the best vector 3 . Studies related to cochlear genetic therapy contribute to the molecular genetic analysis of hearing; experimentally, the skill to introduce genes in the inner ear may lead to elucidation of the function of cochlear proteins and the control of specific inner ear genes 25 . The methods of vector introduction include infusion by mini-probing or microinjection in the tympanic scala, through the round window 25 .…”

Section: Treatment and Perspectivesmentioning

confidence: 99%

“…Studies related to cochlear genetic therapy contribute to the molecular genetic analysis of hearing; experimentally, the skill to introduce genes in the inner ear may lead to elucidation of the function of cochlear proteins and the control of specific inner ear genes 25 . The methods of vector introduction include infusion by mini-probing or microinjection in the tympanic scala, through the round window 25 . It is necessary to make some comments about the disorder.…”

Section: Treatment and Perspectivesmentioning

confidence: 99%

Revisão sobre a perda auditiva na Síndrome de Alport, analisando os aspectos clínicos, genéticos e biomoleculares

Alves¹,

Ribeiro²

2005

Rev. Bras. Otorrinolaringol.

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A Síndrome de Alport é uma desordem hereditária, caracterizada por hematúria, freqüentemente levando à falência renal. Pode ser acompanhada de alterações extra-renais, tais como: perda auditiva (PA) sensório-neural e alterações oculares. São descritas formas dominantes ligadas ao X, devidas às mutações no lócus COL4A5 e uma forma autossômica recessiva resultando de mutações no lócus COL4A3 ou COL4A4. Ainda foi sugerido um tipo autossômico dominante de SA. A doença decorre de alterações nas cadeias de colágeno tipo IV e os sintomas refletem o comprometimento da membrana basal de vários órgãos. As redes alfa3.alfa4.alfa5(IV) ocorrem no rim, na cóclea e no olho. O objetivo foi caracterizar a PA neste grupo de pacientes. Quando o quadro progride para o estágio final de falência renal, o melhor método de tratamento é o transplante, que tem contribuído para o aumento da sobrevida. Nesta revisão bibliográfica, observamos que: 1. A SA caracteriza-se por hematúria, que evolui para falência renal e pode ser acompanhada de manifestações extra-renais. A PA é um achado extra-renal freqüente e um dos primeiros sintomas na SA, sendo um fator relevante para o prognóstico da evolução da doença renal; 2. A SA é genética e decorre da alteração das cadeias do colágeno tipo IV nas membranas basais; 3. A perda auditiva na SA é sensório-neural, de intensidade variável, progressiva e simétrica. Acomete as freqüências médias e altas; 4. Na investigação das perdas auditivas, o otorrinolaringologista deve incluir um exame de urina. É fundamental que o otologista atue no acompanhamento deste grupo de pacientes.

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Cochlear Gene Therapy

Cited by 9 publications

References 0 publications

An in vitro model system to study gene therapy in the human inner ear

An in vitro model system to study gene therapy in the human inner ear

Coxsackie adenovirus receptor and ανβ3/ανβ5 integrins in adenovirus gene transfer of rat cochlea

Revisão sobre a perda auditiva na Síndrome de Alport, analisando os aspectos clínicos, genéticos e biomoleculares

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