GROWTH-RETARDATION - AN UNEXPECTED OUTCOME FROM GROWTH-HORMONE GENE-THERAPY IN NORMAL MICE WITH MICROENCAPSULATED MYOBLASTS

Recently, we have succeeded in using nonautologous myoblasts engineere d to secrete mouse growth hormone (GH) to correct partially the growth retardation of the Snell dwarf mice, which suffer from pituitary GH d eficiency. The allogeneic myoblasts were protected from immune rejecti on by enclosure in permselective microcapsules fabricated from alginat e, thus validating the clinical efficacy of using universal nonautolog ous cells for somatic gene therapy. Because GH therapy is considered a lso for treating patients with normal pituitary function, we now apply this protocol to treat normal mice to evaluate the potential conseque nces of using GH gene therapy in subjects with no demonstrated GH defi ciency. When microencapsulated allogeneic myoblasts engineered to secr ete 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 gro wth plates were less differentiated, indicating reduced skeletal growt h. Females were more severely affected than males and 2 animals died b y day 13 of unknown cause. By day 70, most of the abnormalities were r estored to normal except for body weights, which remained below normal . In conclusion, although somatic gene therapy for GA delivery is bene ficial for pituitary dwarfism, it may have adverse metabolic consequen ces in those with normal hypothalamic-pituitary functions, and the fem ale mice were more severely affected than males.