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Cutting Edge: Treatment of Complement Regulatory Protein Deficiency by Retroviral In Vivo Gene Therapy¹

Dirk Spitzer^2,*, Xiaobo Wu^*, Xiucui Ma, Lingfei Xu, Katherine P. Ponder and John P. Atkinson^2,*

Department of Internal Medicine, ^* Division of Rheumatology and Division of Hematology, Washington University School of Medicine, St. Louis, MO 63110

Gene therapy is an attractive means to replace a deficient or defective protein. Using a murine retroviral vector, we provide an example of reconstituting a C regulator by neonatal in vivo gene transfer. The fusion gene containing the mouse C receptor 1-related gene/protein y (Crry) and a single chain Ab fragment with specificity for mouse glycophorin A was placed under transcriptional control of a liver-specific promoter. Shortly after birth, Crry KO mice were injected with the retroviral vectors. Protein expression progressively increased over the next 6–8 wk after which an equilibrium was established. Coating levels on RBCs were obtained that inhibited C activation similar to wild-type cells and remained constant for >1 year. Thus, gene therapy with targeted regulators represents a treatment option to provide a long-term and sustained protein supply for the site-specific blockade of undesirable complement activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants 5RO1AI37618 and RO1AI41592 (to J.P.A.).

² Address correspondence and reprint requests to Dr. John P. Atkinson, Department of Medicine, Division of Rheumatology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8045, St. Louis, MO 63110; E-mail address: jatkinso{at}im.wustl.edu or Dr. Dirk Spitzer, Department of Medicine, Division of Rheumatology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8045, St. Louis, MO 63110; E-mail address: dspitzer{at}im.wustl.edu

³ Abbreviations used in this paper: aHUS, atypical hemolytic uremic syndrome; AMD, age-related macular degeneration; CCP, C control protein repeat; Crry, complement receptor 1-related gene/protein y; hAAT, human 1 anti-trypsin; PNH, paroxysmal nocturnal hemoglobinuria; scFv, single chain Ab fragment; SEC, sinusoidal endothelial cell; WPRE, woodchuck hepatitis virus posttranscriptional regulatory element; WT, wild type.

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