Article

Adenoviral vectors for improved gene delivery to the inner ear.

Department of Otolaryngology, University of Heidelberg, Germany.
Hearing research (Impact Factor: 2.85). 02/2009; 248(1-2):31-8. DOI: 10.1016/j.heares.2008.11.009
Source: PubMed

ABSTRACT An important requirement for gene therapy in the inner ear is to achieve efficient gene delivery without damaging residual inner ear function. This can be achieved by delivering a high concentration of vector in a minimal volume. Adenovectors are well suited to meet these requirements since high quality concentrated vector with a high capacity for a gene payload can be produced. To reduce the number of vector particles and volume of delivery to the inner ear, we tested vectors with enhancements in cell binding and cell entry properties. We compared delivery of a marker gene to the inner ear using two different advanced generation serotype 5 adenovector designs. The first adenovector tested, AdRGD, has a restricted tropism of entry into cells. AdRGD is an Ad5 capsid vector with an arg-gly-asp (RGD) motif built into the adenovector fiber that has also been modified to abolish the fiber-CAR and penton-integrin interactions that provide the normal well characterized two-step entry pathway for adenovirus. The AdRGD vector has enhanced binding to alphanu integrins. The second vector, AdF2K, contains 7 lysine residues within the fiber knob and has been shown to have expanded tropism for cells in vitro and in vivo. AdF2K maintains its normal CAR and integrin receptors interactions and has an additional mechanism of entry via its ability to interact with heparan sulfate. Both vectors demonstrated effective delivery to the inner ear and more uniform labeling of the inner ear sensory epithelia than native capsid vector, when tested in vivo. Analysis of expression efficiency using quantitative PCR was tested in vitro on cultured macular organs and demonstrated that vector delivery with the AdF2K vector design yielded optimal delivery. The present study demonstrates that retargeting strategies can improve delivery to the inner ear.

0 Followers
 · 
135 Views
  • Source
    • "Several studies in inner ear gene therapy have reported successful delivery of the Atoh1 gene using adenoviral vectors (Huang et al., 2009; Kawamoto et al., 2003; Praetorius et al., 2009; Staecker et al., 2007; Zheng and Gao 2000). Atoh1 is a protein belonging to the basic helix–loop–helix family of transcription factors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Hearing is one of our main sensory systems and having a hearing disorder can have a significant impact in an individual's quality of life. Sensory neural hearing loss (SNHL) is the most common form of hearing loss; it results from the degeneration of inner ear sensory hair cells and auditory neurons in the cochlea, cells that are terminally differentiated. Stem cell-and gene delivery-based strategies provide an opportunity for the replacement of these cells. In recent years, there has been an increasing interest in gene delivery to mesenchymal stem cells. In this study, we evaluated the potential of human umbilical cord mesenchymal stromal cells (hUCMSCs) as a possible source for regenerating inner ear hair cells. The expression of Atoh1 induced the differentiation of hUCMSCs into cells that resembled inner ear hair cells morphologically and immunocytochemically, evidenced by the expression of hair cell-specific markers. The results demonstrated for the first time that hUCMSCs can differentiate into hair cell-like cells, thus introducing a new potential tissue engineering and cell transplantation approach for the treatment of hearing loss.
    02/2013; 15(1):43-54. DOI:10.1089/cell.2011.0097
  • Source
    • "We have evaluated genetic retargeting of standard Ad5 fiber knob domains. Ad5 vectors that showed enhanced binding to heparin were able to transduce vestibular neuroepithelium more efficiently than a vector with enhanced binding to integrins or native capsid vector (Fig 6)(Praetorius et al., 2009a). If supporting cell specific epitopes could be identified, vectors could potentially be made even more specific to their intended target. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the significant impact of hearing and balance disorders on the general population there are currently no dedicated pharmaceuticals that target the inner ear. Advances in molecular biology and neuroscience have improved our understanding of the inner ear allowing the development of a range of molecular targets that have the potential to treat both hearing and balance disorders. One of the principal advantages of the inner ear is that it is accessible through a variety of approaches that would allow a potential to be delivered locally rather than systemically. This significantly broadens the potential medications that can be developed and opens the possibility of local gene delivery as a therapeutic intervention. Several potential clinical targets have been identified including delivery of neurotrophin expressing genes as an adjunct to cochlear implantation, delivery of protective genes to prevent trauma and the development of strategies for regenerating inner ear sensory cells. In order to translate these potential therapeutics into humans we will want to optimize the gene delivery methodology, dosing and activity of the drug for therapeutic value. To this end we have developed a series of adenovectors that efficiently transduce the inner ear. The use of these gene delivery approaches are attractive for the potential of hair cell regeneration after loss induced by trauma or ototoxins. This approach is particularly suited for the development of molecular therapies targeted at the vestibular system given that no device based therapeutic such a cochlear implant available for vestibular loss.
    Hearing research 06/2011; 276(1-2):44-51. DOI:10.1016/j.heares.2011.01.006 · 2.85 Impact Factor
  • Source
Show more

Preview

Download
0 Downloads
Available from