Long-term in vivo cochlear transgene expression mediated by recombinant adeno-associated virus

Ak, Lalwani; Walsh, BJ; Reilly, PG; Carvalho, G J; Zolotukhin, Sergei; Muzyczka, Nicholas; Mhatre, Anand N.

doi:10.1038/sj.gt.3300573

Cited by 84 publications

(68 citation statements)

References 8 publications

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“…Reporter gene expression studies have demonstrated that, amongst other cells and tissues, transgene expression in SGNs and the organ of Corti is commonly obtained [62,[82][83][84][85]. Persistence of transgene expression depends greatly on the mode of delivery and can range from days to months [84,[86][87][88].…”

Section: Delivery Techniques For Neurotrophin Administration In the Cmentioning

confidence: 99%

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Pettingill

Richardson

Wise

et al. 2007

IEEE Trans. Biomed. Eng.

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Spiral ganglion neurons (SGNs) are the target cells of the cochlear implant, a neural prosthesis designed to provide important auditory cues to severely or profoundly deaf patients. The ongoing degeneration of SGNs that occurs following a sensorineural hearing loss is therefore considered a limiting factor in cochlear implant efficacy. We review neurobiological techniques aimed at preventing SGN degeneration using exogenous delivery of neurotrophic factors. Application of these proteins prevents SGN degeneration and can enhance neurite outgrowth. Furthermore, chronic electrical stimulation of SGNs increases neurotrophic factor-induced survival and is correlated with functional benefits. The application of neurotrophic factors has the potential to enhance the benefits that patients can derive from cochlear implants; moreover, these techniques may be relevant for use with neural prostheses in other neurological conditions.

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Section: Delivery Techniques For Neurotrophin Administration In the Cmentioning

confidence: 99%

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Pettingill

Richardson

Wise

et al. 2007

IEEE Trans. Biomed. Eng.

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“…There are many different ways to transduce cochlear tissues, some of which might have more transduction efficiency with less toxicity. Previous studies reported viralmediated gene transfer into the cochlea using herpes simplex type I and vaccinia viruses (Bowers et al 2002;Chen et al 2001;Derby et al 1999;Van de Water et al 1999), lentiviruses (Han et al 1999), retroviruses (Zheng et al 1998), adenoviruses (Jero et al 2001Luebke et al 2001;Mondain et al 1998;Raphael et al 1996;Shou et al 2003;Stover et al 2000), and adenoassociated viruses (Kho et al 2000;Lalwani et al 1998;Stone et al 2005;Luebke et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Functional Prestin Transduction of Immature Outer Hair Cells from Normal and Prestin-Null Mice

Xia

Wooltorton

Palmer

et al. 2008

JARO

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Prestin is a membrane protein in the outer hair cell (OHC) that has been shown to be essential for electromotility. OHCs from prestin-null mice do not express prestin, do not have a nonlinear capacitance (the electrical signature of electromotility), and are smaller in size than wild-type OHCs. We sought to determine whether prestin-null OHCs can be transduced to incorporate functional prestin protein in a normal fashion. A recombinant helper-dependent adenovirus expressing prestin and green fluorescent protein (HDAd-prestin-GFP) was created and tested in human embryonic kidney cells (HEK cells). Transduced HEK cells demonstrated membrane expression of prestin and nonlinear capacitance. HDAd-prestin-GFP was then applied to cochlear sensory epithelium explants harvested from wild-type and prestin-null mice at postnatal days 2-3, the age at which native prestin is just beginning to become functional in wildtype mice. At postnatal days 4-5, we investigated transduced OHCs for (1) their prestin expression pattern as revealed by immunofluorescence; (2) their cell surface area as measured by linear capacitance; and (3) their prestin function as indicated by nonlinear capacitance. HDAd-prestin-GFP efficiently transduced OHCs of both genotypes and prestin protein localized to the plasma membrane. Whole-cell voltage clamp studies revealed a nonlinear capacitance in transduced wild-type and prestin-null OHCs, but not in non-transduced cells of either genotype. Prestin transduction did not increase the linear capacitance (cell surface area) for either genotype. In peak nonlinear capacitance, voltage at peak nonlinear capacitance, charge density of the nonlinear capacitance, and shape of the voltage-capacitance curves, the transduced cells of the two genotypes resembled each other and previously reported data from adult wildtype mouse OHCs. Thus, prestin introduced into prestin-deficient OHCs segregates normally to the cell membrane and generates a normal nonlinear capacitance, indicative of normal prestin function.

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“…31 Like Ad vectors, there is variation in expression profiles among experiments. AAVs can infect nearly all cochlear tissue types, 38,40 or just the SGCs and stria vascularis. 37,39 The reduced immune response, in particular, makes AAVs attractive for further exploration.…”

Section: Adeno-associated Viralmentioning

confidence: 99%

“…In fact, AAVs have been found to mediate gene expression for up to 6 months, albeit at decreased levels. 38 AAV vectors can accommodate DNA of 3.5-4.0 kilobases (kb), 18 sufficient to accommodate the DNA (o3 kb) encoding cytokines and neurotrophins. 37 AAV vectors are less toxic than Ad vectors, 39 although damage to cochlear architecture has been observed in a 24-day study.…”

Section: Adeno-associated Viralmentioning

confidence: 99%

Treatment of peripheral sensorineural hearing loss: gene therapy

Duan

Venail

Spencer³

et al. 2004

Gene Ther

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Noise, chemicals and genetic defects are all common causes of irreversible hearing loss, which at present have no cure. Gene therapy may soon be utilized in both the protection and the treatment of these exogenous and endogenous sources of hearing loss. Gene therapy technology is rapidly developing and the inner ear is a particularly feasible model for gene therapy. This review outlines our current understanding of the mechanisms behind deafness and prospects for treatment, discusses the inner ear model in detail and reviews the efforts that have been made in inner ear gene therapy. Finally, the proposed next steps will be discussed. The viral mediated delivery of neurotrophins and antoxidants offers imminent promise in preventing and treating exogenous hearing loss and improving cochlear implant therapy.

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Long-term in vivo cochlear transgene expression mediated by recombinant adeno-associated virus

Cited by 84 publications

References 8 publications

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System

Functional Prestin Transduction of Immature Outer Hair Cells from Normal and Prestin-Null Mice

Treatment of peripheral sensorineural hearing loss: gene therapy

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