Growth Retardation—An Unexpected Outcome from Growth Hormone Gene Therapy in Normal Mice with Microencapsulated Myoblasts

Abstract

Recently, we have succeeded in using nonautologous myoblasts engineered to secrete mouse growth hormone (GH) to correct partially the growth retardation of the Snell dwarf mice, which suffer from pituitary GH deficiency. The allogeneic myoblasts were protected from immune rejection by enclosure in permselective microcapsules fabricated from alginate, thus validating the clinical efficacy of using universal nonautologous cells for somatic gene therapy. Because GH therapy is considered also for treating patients with normal pituitary function, we now apply this protocol to treat normal mice to evaluate the potential consequences of using GH gene therapy in subjects with no demonstrated GH deficiency. When microencapsulated allogeneic myoblasts engineered to secrete mouse GH were implanted into normal male and female mice, contrary to expectation, the treated animals became significantly shorter and lost weight; their internal organs became smaller and their tibial growth plates were less differentiated, indicating reduced skeletal growth. Females were more severely affected than males and 2 animals died by day 13 of unknown cause. By day 70, most of the abnormalities were restored to normal except for body weights, which remained below normal. In conclusion, although somatic gene therapy for GH delivery is beneficial for pituitary dwarfism, it may have adverse metabolic consequences in those with normal hypothalamic–pituitary functions, and the female mice were more severely affected than males.

Overview summary

“Nonautologous somatic gene therapeutics” is an alternate approach to somatic gene therapy in which universal cell lines engineered to secrete desired gene products are implanted into different recipients with the same product requirement. To prevent immune rejection of nonautologous cell lines, immunoprotective devices such as microcapsules are used to enclose these cells before implantation. The clinical efficacy of this approach has been demonstrated recently when the growth retardation of a dwarf mouse strain with pituitary growth hormone (GH) deficiency was successfully treated using encapsulated recombinant myoblasts. Because GH therapy has been suggested for anabolic uses in humans without pituitary hormone deficiency, it is important to evaluate the efficacy of GH supplement through gene therapy protocols in such “normal” individuals without endogenous GH deficiency. The unexpected growth retardation and other iatrogenic metabolic consequences in the treated animals we now observe should highlight the importance of two issues: preclinical studies in appropriate animal models to test novel treatments in general, and appropriate selection of patients with pituitary GH deficiencies for GH gene therapy in particular.