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

Abstract

An inherited deficiency of acid sphingomyelinase (ASM) activity results in the Type A and B forms of Niemann-Pick disease (NPD). Using the ASM-deficient mouse model (ASMKO) of NPD, we evaluated the efficacy of enzyme replacement therapy (ERT) for the treatment of this disorder. Recombinant human ASM (rhASM) was purified from the media of overexpressing Chinese Hamster ovary 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 sphingomyelin (SPM) content. Notably, the SPM levels were markedly reduced in the hearts, livers, and spleens of these animals, and to a lesser degree in the lungs. Little or no substrate depletion was found in the kidneys or brains. Based on these results, three additional 5-month-old ASMKO animals were injected every other day with 5 mg/kg for 8 days (4 injections) and killed on day 10 for histological analysis. Consistent with the biochemical results, marked histological improvements were observed in the livers, spleens, and lungs, indicating a reversal of the disease pathology. A group of 10 ASMKO mice were then i.v. injected once a week with 1 mg/kg rhASM for 15 wk, starting at 3 wk of age. Although anti-rhASM antibodies were produced in these mice, the antibodies were not neutralizing and no adverse effects were observed 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 histological 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 unlikely to prevent the severe neurodegeneration associated with Type A NPD.

Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann–Pick disease type B (acid sphingomyelinase deficiency)

“…[9][10][11][12][13] Preclinical studies in an ASM knockout mouse model of NPD demonstrated that biweekly administration of olipudase alfa reduced tissue sphingomyelin concentrations in a dosedependent manner. 14,15 No adverse effects were observed at Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann-Pick disease type B (acid sphingomyelinase deficiency)…”

“…14,15 Marked elevations in interleukin (IL)-6, granulocyte colony-stimulating factor, and keratinocyte-derived cytokine were detected within hours of dosing, consistent with cytokine storm. 15 This unexpected toxicity occurred after a single dose of olipudase alfa, precluding the involvement of antibody-mediated pathways.…”

Safety Study of Adeno-Associated Virus Serotype 2-Mediated Human Acid Sphingomyelinase Expression in the Nonhuman Primate Brain

“…Recombinant ASM purified from the culture medium of Chinese hamster ovary (CHO) cells (He et al, 1999) is rapidly taken up from the circulation 1 of ASM knockout mice primarily into liver and spleen, where it is directed to acidified organelles and can degrade SM (Miranda et al, 2000). This finding strongly suggests that enzyme replacement therapy by intravenous infusion of recombinant ASM is a feasible strategy for the treatment of the peripheral symptoms of Niemann-Pick disease as seen in both types A and B.…”

“…This finding strongly suggests that enzyme replacement therapy by intravenous infusion of recombinant ASM is a feasible strategy for the treatment of the peripheral symptoms of Niemann-Pick disease as seen in both types A and B. However, recombinant ASM does not cross the blood-brain barrier and, therefore, this therapy does not appear to improve ASM levels in the brain or reduce SM (Miranda et al, 2000). It is essential, therefore, that alternatives to enzyme replacement therapies be developed to deal with the profound neurological deficits encountered in NPDA.…”

Les sphingolipides : vecteurs d’agents pathogènes et cause de maladies génétiques

“…La plupart sont en effet de type palliatif. Les résultats les plus encourageants sont obtenus par substitution d'enzyme recombinante, glucosidase ou sphingomylinase [41][42][43], et dans une moindre mesure, par diminution du substrat [44][45][46][47]. L'avenir réside dans la mise au point de thérapies géniques visant à réintroduire le gène déficient [48].…”