Engineering targeted viral vectors for gene therapy - PubMed (original) (raw)

Review

Engineering targeted viral vectors for gene therapy

Reinhard Waehler et al. Nat Rev Genet. 2007 Aug.

Abstract

To achieve therapeutic success, transfer vehicles for gene therapy must be capable of transducing target cells while avoiding impact on non-target cells. Despite the high transduction efficiency of viral vectors, their tropism frequently does not match the therapeutic need. In the past, this lack of appropriate targeting allowed only partial exploitation of the great potential of gene therapy. Substantial progress in modifying viral vectors using diverse techniques now allows targeting to many cell types in vitro. Although important challenges remain for in vivo applications, the first clinical trials with targeted vectors have already begun to take place.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. Native entry mechanisms of unmodified viral vectors.

a | Adenovirus (Ad). Ad serotype 5 binds to its receptor CAR (coxsackie and adenovirus receptor) through its fibre knob. Subsequently, integrins interact with the RGD peptide motif in the penton base (the capsid protein at the base of the fibre) and facilitate cell entry by endocytosis. b | Adeno-associated virus (AAV). Several basic residues of the AAV2 (adeno-associated virus serotype 2) capsid protein VP3 (especially positions R585 and R588) are involved in heparin binding. AAV2 first binds to heparan-sulphate proteoglycan (HSPG) and then to the co-receptor, which can be either an integrin (shown here), human fibroblast growth factor receptor or hepatocyte growth factor receptor. The virus is internalized by endocytosis. Other AAV serotypes either resemble AAV2 in its heparin binding (such as AAV3 and AAV6), or use different primary receptors (for example, sialic acid for AAV4 and AAV5). c | Retrovirus (lentivirus): Membrane fusion is the main mechanism whereby enveloped viruses deliver their genomes into target cells. After initial nonspecific adhesion of the virus to the cell surface, viral attachment glycoproteins bind specifically to their cognate receptors, whereupon binding becomes irreversible. The host range of retroviral vectors is determined by the interaction of the viral envelope protein (Env) and the cellular receptor. Subsequent steps in the viral entry process vary between different viruses but always result in fusion between the lipid membranes of the virus and the host cell, following which the viral nucleocapsid is released into the cytoplasm. In some cases, receptor binding triggers conformational changes in the viral proteins that mediate membrane fusion. In others, the cell-bound virus is transported by its receptor into an endosomal compartment where a reduction in pH triggers a conformational rearrangement of the viral fusion machinery. SU, surface subunit; TM, transmembrane subunit.

Figure 2

Figure 2. Targeting options for viral vectors.

Many targeting modalities have been implemented for all three vector types discussed in this Review. The targeting techniques are illustrated for only one viral attachment protein in most of the panels. A |Pseudotyping. A retroviral (lentiviral) vector is pseudotyped with an envelope protein (Env) from a different virus. B |Adaptors. In part Ba, an adenoviral vector is coupled with a receptor–ligand fusion; in this example, the ectodomain of the adenoviral receptor is fused to a ligand that is expressed on a target cell type (for example, CD40L, the ligand for the CD40 receptor on dendritic cells). In part Bb, a biotin-acceptor peptide is integrated into the fibre knob, biotinylated and coupled to an avidin-containing ligand. In part Bc, an antibody-binding domain is genetically incorporated into the adeno-associated virus (AAV) capsid to couple a monoclonal antibody to the vector. In part Bd, a bispecific antibody is attached to the AAV capsid. C | Genetic incorporation of a targeting ligand. In part Ca, a single-chain antibody (single-chain variable fragment (scFv) against human carcinoembryonic antigen (CEA)) and a matrix metalloprotease (MMP) cleavage site are coupled to the viral envelope protein (Env). This allows binding to tumour cells that express CEA, followed by cleavage of the MMP cleavage site by tumour-secreted MMP. The vector can also be targeted to tumour cells by incorporating a tumour-specific scFv directly into Env. However, these insertions can perturb infection if the targeted receptor does not support the required post-binding steps towards viral entry. The MMP cleavage site allows release of the scFv before fusion with the target cell. In part Cb, incorporation of a small targeting ligand (for example, an RGD peptide) can be used to target a vector to integrin receptors. In part Cc, the serotype is changed to achieve desired targeting. In part Cd, the use of different fibres in the same vector allows multifunctionality in a mosaic fibre virus. CAR, coxsackie and adenovirus receptor.

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