Increases in adipose and total body weight, but not in lean body mass, associated with subcutaneous administration of Sonic hedgehog‐Ig fusion protein to mice

Abstract

AbstractSonic hedgehog (Shh) is a member of a family of proteins that are involved in embryonic development. The receptor signaling pathways for Shh persist in adults and stimulation of this pathway has shown therapeutic efficacy in animal models of neurodegeneration/regeneration. This study was conducted to evaluate the safety of repeat dose administration of an IgG fusion protein of Shh (Shh‐Ig) in adult mice. Routine toxicology evaluations were performed. In addition, body composition analysis was conducted by densitometry. Shh‐Ig treatment caused a significant increase in body weight gain relative to controls and a slight increase in liver and spleen weights. The increase in body weight could be largely accounted for by an increase in body fat. The treatment‐related increases in body weight were reversible upon cessation of treatment. Shh‐Ig treatment produced no significant changes in clinical chemistry or hematology. There were no gross or histomorphologic findings in any tissue except for skin and spleen. Microscopic findings in the skin were limited to minimal to slight local epidermal hyperplasia at the sc injection site and increased thickness of the fat layer. In the spleen a slight increase in extramedullary hematopoiesis was seen. This finding is possibly a secondary response following inflammation at the injection site in some animals due to the administration of a foreign protein. This study showed that Shh‐Ig administration was well tolerated. The most significant finding was a reversible increase in body weight. Drug Dev. Res. 57:107–114, 2002. © 2002 Wiley‐Liss, Inc.