Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology

An inherited deficiency of acid sphingomyelinase (ASM) activity results in the Type A and B forms of Niemann-Pick disease (NPD). Using the ASM-deficie nt mouse model (ASMKO) of NPD, we evaluated the efficacy of enzyme replacem ent therapy (ERT) for the treatment of this disorder. Recombinant human ASM (rhASM) was purified from the media of overexpressing Chinese Hamster ovar y cells and i.v. injected into 16 five-month-old ASMKO mice at doses of 0.3 , 1, 3, or 10 mg/kg every other day for 14 days (7 injections). On day 16, the animals were killed and the tissues were analyzed for their sphingomyel in (SPM) content. Notably, the SPM levels were markedly reduced in the hear ts, livers, and spleens of these animals, and to a lesser degree in the lun gs. Little or no substrate depletion was found in the kidneys or brains. Ba sed on these results, three additional 5-month-old ASMKO animals were injec ted every other day with 5 mg/kg for 8 days (4 injections) and killed on da y 10 for histological analysis. Consistent with the biochemical results, ma rked histological improvements were observed in the livers, spleens, and lu ngs, indicating a reversal of the disease pathology. A group of 10 ASMKO mi ce were then i.v. injected once a week with 1 mg/kg rhASM for 15 wk, starti ng at 3 wk of age. Although anti-rhASM antibodies were produced in these mi ce, the antibodies were not neutralizing and no adverse effects were observ ed from this treatment. Weight gain and rota-rod performance were slightly improved in the treated animals as compared with ASMKO control animals, but significant neurological deficits were still observed and their life span was not extended by ERT. In contrast with these CNS results, striking histo logical and biochemical improvements were found in the reticuloendothelial system organs (livers, spleens, and lungs). These studies indicate that ERT should be an effective therapeutic approach for Type B NPD, but is unlikel y to prevent the severe neurodegeneration associated with Type A NPD.