Alexion Pharmaceuticals, Inc.

James M Mason

Stephen P Squinto

Scott P Kennedy

Russell P Rother

Scott A Rollins

Seth A Fidel

Modified retroviral vector particles and modified retroviral producer cells producing such particles are provided for facilitating gene therapy procedures involving the transduction of target cells with retroviral vector particles in the presence of complement containing body fluids. The modifications involve genetic alterations to effect the expression by these cells and particles of complement inhibitor activity. The genetic alterations involve the introduction of nucleic acid expression constructs directing the expression of retroviral SU(gp70)/complement inhibitor chimeric proteins into cells from which the producer cells are derived.

Retroviral vector particles expressing complement inhibitor activity

Retroviral vector particles are provided which contain: 1) oncoretroviral gag, pol, and env proteins, including an oncoretroviral gag capsid protein which has been mutated so as to contain a nuclear localization signal (NLS) sequence; and 2) at least one exogenous gene. The particles can be used to transduce non-proliferating cells, including stem cells and neurons. The presence of the NLS sequence allows the at least one exogenous gene to enter into the nucleus of a target cell, thus allowing integration of the gene into the genome of the target cell.

Retroviral vector particles for transducing non-proliferating cells

Retroviral vector particles are provided which contain: 1) oncoretroviral gag, pol, and env proteins, including an oncoretroviral gag matrix protein which has been mutated so as to contain a nuclear localization signal (NLS) sequence; and 2) at least one exogenous gene. The particles can be used to transduce non-proliferating cells, including stem cells and neurons. The presence of the NLS sequence allows the at least one exogenous gene to enter into the nucleus of a target cell, thus allowing integration of the gene into the genome of the target cell.

Methods and compositions are provided for facilitating gene therapy procedures involving the transduction of target cells with retroviral vector particles in the presence of complement containing body fluids. The administration of soluble complement inhibitor molecules to body fluids prevents the complement mediated inactivation of the retroviral vector particles, and provides a safety mechanism for such gene therapy procedures, as the action of soluble complement inhibitors is transient, and any retroviral vector particles present after the return of uninhibited complement activity will be inactivated. Preferred soluble complement inhibitors for use in the practice of the present invention include complement inhibitory anti-complement component mAbs (including complement inhibitory anti C5 antibodies).

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Wallingford, CT, United States of America

James M Mason