Gain-of-Function Mutations and Therapeutic Implications

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 …