Use of ACTIMMUNE in Patients With ADO2

This is a single center, open-label, dose-escalation study evaluating the efficacy, as defined by biochemical endpoints, and safety profiles of ACTIMMUNE in ADO2 subject.

The investigators will treat 12 ADO2 subjects (children or adults age 3-65) with Actimmune® via a dose escalation protocol to a dose of 50 µg/m2 subcutaneously three times per week (TIW) for 8 weeks. If serum CTX does not increase by more than 25% by week 8, the dose will be increased to 100 µg/m2 subcutaneously TIW.

Individual subjects in whom ACTIMMUNE administration increases bone resorption markers during the 14 weeks of this trial will be eligible for a 1 year extension trial.

Inclusion criteria

• Subject is diagnosed with clinically significant ADO2 as determined by the investigator.

Individuals will be screened who have either been diagnosed with osteopetrosis and have a clinical phenotype and/or family history that is consistent with ADO2, have been told that they have an abnormally high bone density (>3SD above mean for age and sex), or a clinical presentation consistent with ADO2. Initial contact will be with members of ADO2 kindreds who have known disease.

• Provide written informed consent for competent adults and for minors provide written assent (if appropriate) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures
• Ages 3 to 65 years inclusive.
• Willing to use reliable method of contraception [i.e. oral or patch hormonal contraceptives, intrauterine device, physical barrier methods, tubal ligation or hysterectomy, vasectomy (partner) or abstinence] throughout the study and for 30 days after the last dose of study drug.

Exclusion criteria

• Any unstable illness that in the investigator's opinion precludes participation in the study.
• Serum calcium >10.6 mg/dl at screening.
• eGFR using the MDRD equation in adults (or the modified Schwartz equation for children) of < 35 ml/min/1.73m2.
• Nephrocalcinosis on screening ultrasound Grade 3 or higher [18]. Subjects with grade 3 or higher nephrocalcinosis will be excluded because we anticipate that use of study drug will increase bone resorption, resulting in increased urinary calcium excretion, which could, potentially, lead to worsening nephrocalcinosis. The grading scale is listed below:

0 = Normal

• = Faint hyperechogenic rim around the sides and tip of the medullary pyramids
• = More intense echogenic rim with echoes faintly filling the entire medullary pyramid
• = Intense echoes throughout the medullary pyramid
• = Solitary focus of echoes at the tip of the medullary pyramid/nephrolithiasis

• Use of any investigational product (drug or device) within 30 days prior to randomization.

• Subject reported history of hepatitis C.

• A recent (past 5 years) history of alcoholism or intravenous drug abuse.

• History of hypersensitivity to IFN-ɣ or E. coli-derived products.

• History of liver disease as evidenced by laboratory results at Screening (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >2x the upper limit of normal), except when in the opinion of the investigator the liver disease is caused by extra medullary hematopoiesis.

• Pregnant or nursing women or those who plan on becoming pregnant during the study.