INTRATHECAL ADMINISTRATION OF RECOMBINANT HUMAN SUPEROXIDE-DISMUTASE-1 IN AMYOTROPHIC-LATERAL-SCLEROSIS - A PRELIMINARY SAFETY AND PHARMACOKINETIC STUDY

We undertook a safety and pharmacokinetic study of intrathecal (IT) re combinant human superoxide dismutase (rhSOD1). We administered rhSOD1 as an acute bolus in three sheep and 16 human subjects with amyotrophi c lateral sclerosis (ALS). Two sheep received chronic IT infusion of r hSOD1 (one at 17.7 mg per day, the second at 38.0 mg per day) for six months. Two of the 16 subjects had familial ALS and mutations in the g ene for Cu/Zn SOD1. They both received IT infusion of rhSOD1 (5 to 10 mg per day) for 3 to 6 months. Intrathecal rhSOD1 administration was s afe. Bolus IT administration of 0.25 mg rhSOD1 in sheep revealed a mea n elimination half-life of 0.4 (SD +/- 0.06) hours, clearance of 12.2 +/- 3.2 ml per hour, and volume of distribution of 7.3 +/- 0.9 ml. Aft er chronic IT infusion, the initial alpha-phase half-life was estimate d as 1.2 hours and the extended beta-phase half-life was 15.0 hours. T he mean clearance rate was 25.9 ml per hour and the steady-state volum e of distribution was 920.6 ml. Bolus IT administration of 20 mu g of rhSOD1 in ALS subjects revealed a mean elimination half-life of 2.2 +/ - 0.8 hours, clearance of 1.2 +/- 0.6 ml per hour, and volume of distr ibution of 3.5 +/- 0.4 ml, With chronic IT infusion of 5 mg per day, c erebrospinal SOD1 levels increased approximately fortyfold. We detecte d no benefit of this treatment in the two patients with familial ALS.