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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2018.)
© 2005 American Heart Association, Inc.

Editorials

Gain-of-Function Mutations and Therapeutic Implications

Lipoprotein Lipase S447X to the Rescue

Daniel J. Rader

From the Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Daniel Rader, MD, University of Pennsylvania Medical Center, 654 BRBII/III, Philadelphia, PA 19104-6160. E-mail rader@mail.med.upenn.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Somatic gene transfer has been extensively used to express genes of interest and probe the molecular physiology of lipoprotein metabolism and many other processes in animal models.¹ Among its advantages over germ-line transgenic animals are the ability to rapidly express genes on selected genetic backgrounds without time-intensive backcrossing, the greater ability to control expression level through dosing of the gene transfer vector, and the greater ability to directly compare 2 genes, or 2 variants of the same gene, with regard to their effects in vivo. The latter advantage has not been fully exploited in the investigation of the functional consequences of naturally occurring human mutations.

See page 2143

In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology is a report by Ross and colleagues of the rescue of lipoprotein lipase (LPL)-deficient mice from lethality using neonatal intramuscular injection of an adenoviral vector to achieve somatic gene transfer and expression of a naturally occurring gain-of-function mutant of LPL.² This report presents a variety of important issues for investigators interested in lipoprotein metabolism as well as those generally interested in somatic gene transfer and therapy. Unlike in humans, LPL deficiency in mice is lethal within the first 48 hours of birth.^3,4 Whereas a previous study demonstrated that neonatal intraperitoneal administration of an adenoviral vector encoding wild-type LPL rescued 3% of the mice to adulthood,⁵ the current study achieved 95% rescue to adulthood. The major difference appears to be that Ross et al used a naturally-occurring variant of LPL, known as S447X, that . . . [Full Text of this Article]

Related Article:

Complete Rescue of Lipoprotein Lipase–Deficient Mice by Somatic Gene Transfer of the Naturally Occurring LPL^S447X Beneficial Mutation

Colin J.D. Ross, Guoqing Liu, Jan Albert Kuivenhoven, Jaap Twisk, Jaap Rip, Willemijn van Dop, Katherine J.D. Ashbourne Excoffon, Suzanne M.E. Lewis, John J. Kastelein, and Michael R. Hayden
Arterioscler Thromb Vasc Biol 2005 25: 2143-2150. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				R. A. Hegele, C. J.D. Ross, J. Twisk, J. A. Kuivenhoven, J. Rip, J. J. Kastelein, and M. R. Hayden Gene therapy with lipoprotein lipase variant S447X. Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): e25 - e25. [Full Text] [PDF]