Local delivery of reporter gene to the cochlea does not spread to brain tissue in an animal model

Duan, Maoli; Mi, Qiang

doi:10.3109/00016480902963053

Cited by 10 publications

(4 citation statements)

References 17 publications

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“…One group transduced immature cochlear cells in utero, showing transgene expression and hearing impairment (Bedrosian et al 2006), but did not explore the capacity to transduce postnatal OC cells. Three additional reports did not find evidence of OC transduction after perilymph injection (Han et al 1999;Pietola et al 2008;Duan and Mi 2010). Han et al (1999) also used LV in postnatal cochlear explants but with a lower dose and different administration showing low rate of transduction in the OC and no HC transduction.…”

Section: Discussionmentioning

confidence: 99%

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p27Kip1 Knockdown Induces Proliferation in the Organ of Corti in Culture after Efficient shRNA Lentiviral Transduction

Maass

Berndt

Cánovas

et al. 2013

JARO

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The cells in the organ of Corti do not exhibit spontaneous cell regeneration; hair cells that die after damage are not replaced. Supporting cells can be induced to transdifferentiate into hair cells, but that would deplete their numbers, therefore impairing epithelium physiology. The loss of p27Kip1 function induces proliferation in the organ of Corti, which raises the possibility to integrate it to the strategies to achieve regeneration. Nevertheless, it is not known if the extent of this proliferative potential, as well as its maintenance in postnatal stages, is compatible with providing a basis for eventual therapeutic manipulation. This is due in part to the limited success of approaches to deliver tools to modify gene expression in the auditory epithelium. We tested the hypothesis that the organ of Corti can undergo significant proliferation when efficient manipulation of the expression of regulators of the cell cycle is achieved. Lentiviral vectors were used to transduce all cochlear cell types, with efficiencies around 4 % for hair cells, 43 % in the overall supporting cell population, and 74 % within lesser epithelial ridge (LER) cells. Expression of short hairpin RNA targeting p27Kip1 encoded by the lentiviral vectors led to measurable proliferation in the organ of Corti and increase in LER cells number but not hair cell regeneration. Our results revalidate the use of lentiviral vectors in the study and in the potential therapeutic approaches for inner ear diseases, as well as demonstrate that efficient manipulation of p27Kip1 is sufficient to induce significant proliferation in the postnatal cochlea.

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Section: Discussionmentioning

confidence: 99%

“…Nevertheless, these vectors have not been successful in transducing the postnatal OC. Studies reported poor results, with lack of transduction of HC in vitro and lack of reaching the OC in vivo (Han et al 1999;Pietola et al 2008;Duan and Mi 2010).…”

Section: Introductionmentioning

confidence: 99%

p27Kip1 Knockdown Induces Proliferation in the Organ of Corti in Culture after Efficient shRNA Lentiviral Transduction

Maass

Berndt

Cánovas

et al. 2013

JARO

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“…In vitro infection of cochlear explants from neonatal rats allowed successful transduction of SGNs and some supporting cells, but not of hair cells (145). One report demonstrated that lentivirus injected into the rat scala tympani remained within the cochlea, with no evidence of its spread to the central nervous system; this is an important feature with regards to minimizing toxicity to tissues outside the cochlea and provides further support for the safety of innerear, viral-mediated gene delivery (95).…”

Section: Viral Vectorsmentioning

confidence: 99%

Toward Cochlear Therapies

Wang

Puel

2018

Physiological Reviews

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Sensorineural hearing impairment is the most common sensory disorder and a major health and socio-economic issue in industrialized countries. It is primarily due to the degeneration of mechanosensory hair cells and spiral ganglion neurons in the cochlea via complex pathophysiological mechanisms. These occur following acute and/or chronic exposure to harmful extrinsic (e.g., ototoxic drugs, noise...) and intrinsic (e.g., aging, genetic) causative factors. No clinical therapies currently exist to rescue the dying sensorineural cells or regenerate these cells once lost. Recent studies have, however, provided renewed hope, with insights into the therapeutic targets allowing the prevention and treatment of ototoxic drug- and noise-induced, age-related hearing loss as well as cochlear cell degeneration. Moreover, genetic routes involving the replacement or corrective editing of mutant sequences or defected genes are showing promise, as are cell-replacement therapies to repair damaged cells for the future restoration of hearing in deaf people. This review begins by recapitulating our current understanding of the molecular pathways that underlie cochlear sensorineural damage, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. It then guides the reader through to the recent discoveries in pharmacological, gene and cell therapy research towards hearing protection and restoration as well as their potential clinical application.

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“…For example, how effective and specific are various viruses, including adenovirus, lentivirus, and many subtypes of AAVs, in infecting the mature organ of Corti? Many studies showed inconsistent transduced cell groups and varied transduction efficiency (Akil et al, 2012; Duan et al, 2010; Han et al, 1999; Kho et al, 2000; Kilpatrick et al, 2011; Konishi et al, 2008; Liu et al, 2005; Luebke et al, 2001; Mondain et al, 1998; Stone et al, 2005), resulting from different ex vivo or in vivo conditions, different animal models, different expressing vectors, different viral diffusion rates, etc. Moreover, will the virus affect other cells and cause permanent genetic changes?…”

Section: Clinical Applicationsmentioning

confidence: 99%

Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development?

Zheng

Zuo

2017

Hearing Research

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Noise-induced hearing loss (NIHL) affects a large number of military personnel and civilians. Regenerating inner-ear cochlear hair cells (HCs) is a promising strategy to restore hearing after NIHL. In this review, we first summarize recent transcriptome profile analysis of zebrafish lateral lines and chick utricles where spontaneous HC regeneration occurs after HC damage. We then discuss recent studies in other mammalian regenerative systems such as pancreas, heart and central nervous system. Both spontaneous and forced HC regeneration occurs in mammalian cochleae in vivo involving proliferation and direct lineage conversion. However, both processes are inefficient and incomplete, and decline with age. For direct lineage conversion in vivo in cochleae and in other systems, further improvement requires multiple factors, including transcription, epigenetic and trophic factors, with appropriate stoichiometry in appropriate architectural niche. Increasing evidence from other systems indicates that the molecular paths of direct lineage conversion may be different from those of normal developmental lineages. We therefore hypothesize that HC regeneration does not have to follow HC development and that epigenetic memory of supporting cells influences the HC regeneration, which may be a key to successful cochlear HC regeneration. Finally, we discuss recent efforts in viral gene therapy and drug discovery for HC regeneration. We hope that combination therapy targeting multiple factors and epigenetic signaling pathways will provide promising avenues for HC regeneration in humans with NIHL and other types of hearing loss.

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Local delivery of reporter gene to the cochlea does not spread to brain tissue in an animal model

Abstract: The patterns of the fluorescent signals with red and green filters were compared to identify the GFP signals in the brain tissue. GFP reporter gene expression was not detected in any examined brain region in any of the animals.

Cited by 10 publications

References 17 publications

p27Kip1 Knockdown Induces Proliferation in the Organ of Corti in Culture after Efficient shRNA Lentiviral Transduction

p27Kip1 Knockdown Induces Proliferation in the Organ of Corti in Culture after Efficient shRNA Lentiviral Transduction

Toward Cochlear Therapies

Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development?

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