Prospective study of neurological responses to treatment with macrophage‐targeted glucocerebrosidase in patients with type 3 Gaucher's disease

Abstract

We prospectively evaluated the clinical and biochemical responses to enzyme-replacement therapy (ERT) with macrophage-targeted glucocerebrosidase (Ceredase) infusions in 5 patients (age, 3.5-8.5 years) with type 3 Gaucher's disease. The patients were followed for up to 5 years. Enzyme dosage ranged from 120 to 480 U/kg of body weight/month. Systemic manifestations of the disease regressed in all patients. Neurological deficits remained stable in 3 patients and slightly improved in 1. One patient developed myoclonic encephalopathy. Cognitive deterioration occurred in 1 patient and electroencephalographic deterioration in 2. Sequential cerebrospinal fluid (CSF) samples were obtained during the first 3 years of treatment in 3 patients and were analyzed for biochemical markers of disease burden. Glucocerebroside and psychosine levels were not elevated in these specimens, whereas chitotriosidase and quinolinic acid were elevated in 2 patients. Progressive decrease in the CSF levels of these latter macrophage markers during 3 years of treatment implies a decreased number of Gaucher cells in the cerebral perivascular space. Similar changes were not observed in the patient who had a poor neurological outcome. In conclusion, ERT reverses systemic manifestations of type 3 Gaucher's disease and appears to reduce the burden of Gaucher cells in the brain-CSF compartment in some patients.

Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines

“…85,86 This approach may change in type III disease as ERT results are closely scrutinized and if HCT techniques improve. 87 The only experimental indication for HCT at present is in type III children who deteriorate neurologically and/or have pulmonary compromise while on ERT. 87,88 a-mannosidosis At this time, fewer than 20 cases have been transplanted in the world.…”

“…87 The only experimental indication for HCT at present is in type III children who deteriorate neurologically and/or have pulmonary compromise while on ERT. 87,88 a-mannosidosis At this time, fewer than 20 cases have been transplanted in the world. Pulmonary complications may be increased during the first several months after HCT.…”

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

“…While effective in managing the visceral symptoms of the disease, enzyme replacement therapy is expensive and cannot address the neurological defects because the replacement enzyme is unable to cross the blood-brain barrier [4]. Treatment with the iminosugar N-butyldeoxynojirimycin (NB-DNJ, Miglustat), an inhibitor of glucosylceramide synthase, has been shown to improve liver and spleen volume and hematological parameters in type 1 Gaucher patients [5].…”

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

“…ERT improves the visceral and hematologic manifestations of the disease, but it is costly and not effective in neuronopathic forms of Gaucher disease because of the inability of recombinant enzymes to cross the blood-brain barrier (10). Miglustat (N-butyldeoxynojirimycin), an iminosugar inhibitor of glucosylceramide synthase, also produces clinical improvement in selected patients with mild or moderate disease, but the responses are slower and less robust than those observed with ERT (11)(12)(13)(14).…”