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Considerations and challenges for the achievement of targeted gene delivery

Gene Therapy volume 6, pages 1497–1498 (1999)Cite this article

An accumulating body of data in human systems has suggested the importance of improving viral vector design via tropism-modification maneuvers.1,2,3 In the first instance, the demonstration of vector-associated toxicities has highlighted the deleterious effects of gene delivery to ectopic sites. On this basis, cell-specific vector-mediated transduction would, theoretically, circumvent this issue. As well, basic vector efficiencies may be suboptimal if subservient exclusively to native viral receptor limits. Thus, infectivity-enhanced vectors could also have improved potency, thus potentially allowing the achievement of a more useful therapeutic index. Clearly, the need for vector targeting is one of the most unambiguous lessons to derive from human clinical trials endeavored heretofore.

Fundamental to any attempts to retarget viruses is a basic understanding of the native determinants of their tropism. Thus, retargeting of retroviral vectors via envelope engineering strategies was based on a highly characterized understanding of the molecular basis of retroviral infection. In a similar manner, the advances in retargeting adenoviral vectors have been firmly grounded in basic virology and cell biology understandings of the relevant processes. In this regard, tropism-modification strategies based on genetic capsid modification have derived from contemporary revelations regarding key structural features of the capsid proteins. Likewise, molecular complex-based retargeting schemes for adenovirus (Ad) vectors have capitalized on the delineation of Ad entry as a two-step process, whereby internalization could be uncoupled from binding. Indeed, the needs of vector development have often been the key catalyst for the definition of relevant biology pursuant to vector design.

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References

  1. Grubb BR et al. Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans Nature 1994 371: 802–806

    Article  CAS  PubMed  Google Scholar 

  2. Crystal RG et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis [see comments] Nat Genet 1994 8: 42–51

    Article  CAS  PubMed  Google Scholar 

  3. Pickles RJ et al. Limited entry of adenovirus vectors into well-differentiated airway epithelium is responsible for inefficient gene transfer J Virol 1998 72: 6014–6023

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Vanderkwaak TJ et al. An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches Gynecologic Oncology (in press)

  5. Dmitriev I et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism J Virol 1998 72: 9706–9713

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kasono K et al. Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector Clin Cancer Res (in press)

  7. McDonald D et al. Coxsackie and adenovirus receptor (CAR)-dependent and major histocompatibility complex (MHC) class I-independent uptake of recombinant adenoviruses into human tumour cells Gene Therapy 1999 6: 1512–1519

    Article  CAS  PubMed  Google Scholar 

  8. Bergelson JM et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5 Science 1997 275: 1320–1323

    Article  CAS  PubMed  Google Scholar 

  9. Hong SS et al. Adenovirus type 5 fiber knob binds to MHC class stoid cells EMBO J 1997 16: 2294–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fechner H et al. Expression of coxsackie-adenovirus-receptor and αv-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers Gene Therapy 1999 6: 1520–1535

    Article  CAS  PubMed  Google Scholar 

  11. Smith AE . Viral vectors for gene therapy Ann Rev Microbiol 1995 49: 807–838

    Article  CAS  Google Scholar 

  12. Reynolds PN, Curiel DT . Strategies to adapt adenoviral vectors for gene therapy applications: targeting and integration. In: Friedmann T (ed) The Development of Human Gene Therapy Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York 1998 111–130

    Google Scholar 

Download references

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  1. University of Alabama at Birmingham, Gene Therapy Center, 1824 6th Avenue South, WT1 620, Birmingham, 35294, AL, United States

    D T Curiel MD

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Curiel, D. Considerations and challenges for the achievement of targeted gene delivery. Gene Ther 6, 1497–1498 (1999). https://doi.org/10.1038/sj.gt.3301038

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