Gene Therapy: Delivery Targeting


Delivery targeting is a novel approach for the design and administration of therapeutic agents wherein the agent is rationally designed to localize to the site of disease in a self‐directed manner, usually via exploitation of unique biophysical properties of the diseased tissue.

Keywords: adenovirus; targeting; gene therapy; tropism modification; cancer

Figure 1.

A generalized adenovirus structure depicting major structural components of a wild‐type adenovirus capsid. Hexon is depicted as a hexagon with 12 homotrimers per capsid face (only 12 of 240 trimers are shown). The penton‐base, comprised of five subunits at each vertex, and trimeric fibre and pIX structures are shown. Adenovirus serotype 2 and 5 capsids contain a 36‐kilobase double‐stranded DNA genome (not shown).

Figure 2.

A schematic representation of genetically altered fibres for adenovirus targeting. (See text for specific examples of each genetic targeting approach and targeting moiety used.) (a) Trimeric wild‐type adenovirus fibre; tail, shaft and knob regions are shown. (b) Pseudotyped chimaeric fibre bearing an alternate human or animal serotype knob domain. (c) Fibre knob containing a C‐terminal targeting ligand. (d) Fibre knob with a constrained targeting peptide in the flexible H–I loop. (e) ‘de‐knobbed’ fibre containing a heterologous trimerization sequence and a C‐terminal targeting moiety.

Figure 3.

The two‐step adenovirus infection pathway. Shown are the basic steps of initial high‐affinity binding of the virion fibre to its primary cellular receptor, CAR, followed by endocytic cell entry mediated by penton‐base RGD interaction with cell‐surface integrins. Upon endosomal lysis, the partially dismantled virion is then released into the cytoplasm and is actively translocated to the nuclear pore complex where complete capsid degradation and viral genome import is accomplished.

Figure 4.

Adapter molecules for receptor‐specific adenovirus targeting. A generalized adapter molecule ablates native CAR‐based tropism and targets adenovirus to an alternate cellular receptor molecule. The dual specificity of the adapter molecule for both the adenovirus and the alternative receptor provides novel, CAR‐independent cell binding.



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Further Reading

Curiel DT and Douglas JT (eds) (2002) Adenoviral Vectors for Gene Therapy. New York: Academic Press.

Curiel DT and Douglas JT (eds) (2002) Vector Targeting for Therapeutic Delivery. Hoboken, NJ: Wiley‐Liss, Inc.

Glasgow JN, Everts M and Curiel DT (2006) Adenovirus targeting. Cancer Gene Therapy 13(9): 830–844.

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Glasgow, Joel N, Beatty, Matthew S, and Curiel, David T(Sep 2007) Gene Therapy: Delivery Targeting. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005746.pub2]