PEDIATRIC PHARMACOLOGY AND THERAPEUTICS Recombinant human interferon therapy for osteopetrosis gamma L. Lyndon Key, Jr., MD, William L. Ries, DDS, PhD, Ramona M. Rodriguiz, BS, and Heather C. Hatcher, BS From the Division of Endocrinology, Department of Pediatrics, Medical University of South Carolina, Charleston A defect in leukocytic superoxide formation has been demonstrated in patients with congenital osteopetrosis. This leukocyte defect appears to be related to defective bone resorption. Because recombinant human interferon gamma therapy enhances superoxide production in patients with chronic granuloma- tous disease, we sought to determine whether a similar strategy could reverse the osteopetrotic condition. Interferon gamma, 1.5 ~g/kg three times a week, was administered by subcutaneous injection for 6 months to eight patients with osteopetrosis. Urinary hydroxyproline and urinary calcium excretion increased markedly during therapy in parallel with a significant decrease in trabecular bone volume. Bone marrow scans demonstrated increased bone marrow pro- duction. The hemoglobin concentration, platelet count, and leukocyte produc- tion of superoxide increased significantly. No serious infections were encoun- tered during the therapy. These data suggest that interferon gamma adminis- tration enhances bone resorption and leukocyte function in patients with osteopetrosis. (J PEDIATR 1992;121:119-24) Osteopetrosis is a disease of deficiencies in bone resorption 1 and leukocyte function.2, 3 The defect in bone resorption re- sults in an increased accumulation of bone, causing a nar- rowing of cranial nerve foramina and a reduction in the marrow cavity.4, s Reduced superoxide generation by leu- kocytes results in an immunodeficiency analogous to, but less severe than, chronic granulomatous disease. 2, 3 These defects cause blindness, deafness, marrow failure, and increased risk of infection. The life expectancy of osteo- petrotic patients is less than 10 years. 6 In patients who are without the option of bone marrow transplantation 4 or who do not respond to high doses of calcitriol,6 there has been no therapeutic alternative. Supported by March of Dimes grant No. 675; U.S. Food and Drug Administration Orphan Drug grant No. FD-R000768; the Chil- dren's Hospital Fund of the Medical Universityof South Carolina, and a General Clinical Research Center grant, Medical University of South Carolina M01-RR-01070= 16. Submitted for publication Feb. 6, 1992; accepted March 6, 1992. Reprint requests: L. Lyndon Key, Jr., MD, Department of Pediat- rics, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425. 9/20/37697 Patients with CGD respond to the subcutaneous admin- istration of recombinant human interferon gamma, 7 which stimulates superoxide production by leukocytes. The dis- covery of a role for superoxide in bone resorption8 led us to hypothesize that bone resorption, as well as leukocyte func- tion, could be improved by the administration of IFN-3, to patients with osteopetrosis. CGD IFN-,y NBT PTH Chronic granulomatous disease Recombinant human interferon gamma Nitroblue tetrazolium Parathyroid hormone METHODS Eight patients ranging in age from 1 month to 11 years (3.0 + 3.9 years) met the entry criteria for inclusion in a trial of therapy with IFN-~/(Actimmune; Genentech). To qualify for entry, patients were required to have a diagnosis of osteopetrosis that had been confirmed by a bone biopsy, evidence of hematologic or neurologic compromise, and a significant increase in nitroblue tetrazolium reduction by cultured hematopoietic cells in response to IFN-~ exposure in vitro. Eight of ten patients screened met the entry crite- 119