Chemistry: molecular biology and microbiology – Treatment of micro-organisms or enzymes with electrical or... – Modification of viruses
Patent
1997-06-09
1999-01-12
Mosher, Mary E.
Chemistry: molecular biology and microbiology
Treatment of micro-organisms or enzymes with electrical or...
Modification of viruses
4352351, 435325, 435366, 435372, 4353201, 435 914, 424 932, 424 9321, C12N 1500, C12N 1563, C12N 1586, C12N 701, C12N 510
Patent
active
058587438
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of international application PCT/GB95/01506 filed Jun. 27, 1995 which designated the United States, and entered the national phase in the U.S. on Dec. 27, 1996.
FIELD OF THE INVENTION
This invention relates to viral particles capable of delivering nucleic acids, compositions comprising such viral particles, and to methods of altering the host Well range of such viruses.
BACKGROUND OF THE INVENTION
Retroviral vectors derived from C-type murine leukaemia viruses (MLVs) have emerged as highly versatile gene delivery vehicles and have been selected for use in many human gene therapy protocols, especially those requiring transduction of normal or neoplastic haemopoietic cells. In the interests of safety and efficacy, particularly for direct genetic modification of target cells in vivo, it is desirable that retroviral gene delivery should be accurate but the clinically approved (amphotropic) retroviral vectors in current use attach to an ubiquitously expressed cellular receptor and therefore infect human cells promiscuously. Cell-selective retroviral gene delivery might be achieved by modification of the viral membrane spike glycoproteins responsible for receptor-mediated virus entry.
Retroviral envelope glycoproteins mediate specific viral attachment to cell surface receptors and subsequently trigger fusion between the viral envelope and the target cell membrane. Retroviral envelope glycoproteins consist of an external glycoprotein moiety (SU) noncovalently attached at its C-terminus to a smaller transmembrane polypeptide moiety (TM). Each surface projection (or spike), visible by electron microscopy on the viral surface is a trimer of identical envelope glycoprotein subunits. SU comprises two domains connected by a proline-rich hinge, the N-terminal domain conferring receptor specificity and exhibiting a high degree of conservation between MLV's with different host ranges (Battini et al. 1992 J Virol 66 p1468-1475).
The crystallisation of retroviral SU proteins or their domains remains elusive but sequence alignment of the SU receptor-binding domains of C-type retroviruses reveals a high degree of homology, presumably reflecting a conserved 3-dimensional fold. Two discontinuous hypervariable peptide sequences in this domain, VRA and VRB, have been identified as major determinants of receptor-binding specificity (Battini et al, 1995 J Virol 69 p713-719). Thus it is probable that these receptor binding domains consist of a conserved framework acting as a scaffold for presentation of hypervariable peptide loops which confer binding specificity. According to the "canyon hypothesis", the receptor binding site in SU is likely to take the form of a pocket or groove whose walls and floor may be formed by the residues in VRA and VRB.
Retroviral host range is determined in part by the species and tissue distribution of specific cell surface receptors that are recognised by the viral envelope glycoprotein. Moloney MLV is an ecotropic virus whose envelope attaches to mouse and rat cells but not to human cells. 4070A MLV is an amphotropic virus whose envelope attaches to cells of mouse and human origin. Three C-type retrovirus receptors have now been identified and all are membrane permeases with multiple membrane-spanning domains. In the case of Moloney MLV, the precise target for virus attachment is a constrained peptide loot in the third extracellular domain of the murine cationic amino acid transporter (CAT1) which also functions as a Moloney virus receptor when transplanted into the corresponding site on a homologous human protein (Albritton et al, 1993 J Virol 67 p2091-2096).
Naturally occurring retroviruses incorporate a single species of envelope glycoprotein which mediates specific high-affinity binding to a single well-defined cognate cell-surface receptor. However, additional receptor-binding domains can be incorporated to generate retroviral particles that are capable of binding to more than one species of cellular receptor. Thus, with dual viral infection of a singl
REFERENCES:
patent: 5559099 (1996-09-01), Wickham et al.
Chu, et al: "Cell targeting with retroviral vector particles containing antibody-envelope fusion proteins", Gene Therapy, vol. 1, 1994, pp. 292-299; see the whole document.
Collins Mary Katharine L.
Cosset Francois-Loic
Morling Frances Joanne
Russell Stephen James
Weiss Robin Anthony
Medical Research Council
Mosher Mary E.
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