PHARMACOKINETICS AND TOLERABILITY OF VENTRICULARLY ADMINISTERED SUPEROXIDE-DISMUTASE IN MONKEYS AND PRELIMINARY CLINICAL OBSERVATIONS IN FAMILIAL ALS

The discovery of mutations in the gene for Cu/Zn superoxide dismutase (SOD) in some cases of familial amyotrophic lateral sclerosis (FALS) p rovides a rationale for enzyme replacement therapy. The inability of S OD to cross the blood-brain barrier motivated this study of the safety , tolerability and pharmacokinetics of bovine SOD (bSOD) administered into the CSF of rhesus monkeys and one late-stage, SOD-deficient FALS patient. Kinetic analyses in the patient indicated that intracerebrove ntricular (i.c.v.) administration, but not lumbar administration, deli vered bSOD to the entire CSF pathway. Daily bolus i.c.v. injections (3 2 mg/day) and continuous i.c.v. infusion (30 mg/day) were well tolerat ed by the patient. During the period of daily bolus injections, the pa tient's performance on manual muscle tests was nearly stable, in contr ast with the rapid decline before and after that period. These results justify further investigation of bSOD therapy in SOD-deficient FALS p atients.