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Gaucher disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Clinical responses to enzyme replacement therapy have been clearly evident in hematologic (anemia and thrombocytopenia), visceral, and even (with longer courses of treatment) bony disease. Decrease in organ size is evident within six months. Bone pains and crises diminish or disappear within 12–24 months [19], and, at least in children, roentgenograms of the bones have improved after years of treatment. Growth and development regularly improve. The treatment is expensive. There is still some controversy as to dose. The dose generally employed is 60 U/kg every two weeks [48], but 30 U/kg every two weeks may also be effective. Experience with 26 years of the use with imiglucerase [88] has led to excellent safety and efficiency. Dosage varied from 15 to 120 U/kg every other week, but the usual dosage was 60 U/kg. Enzyme replacement therapy has been judged [89] ineffective in intraalveolar pulmonary disease.
Current and emerging pharmacotherapy for Gaucher disease in pediatric populations
Published in Expert Opinion on Pharmacotherapy, 2021
Richard Sam, Emory Ryan, Emily Daykin, Ellen Sidransky
Despite the high cost, most Gaucher centers begin children with symptomatic GD on higher dosages of ERT, starting at 60 U/kg every other week, compared to 30–60 U/kg every other week for adults. While in early years, some groups advocated for frequent infusions of much lower doses of ERT, this is now rarely implemented. Qiu et al reported a retroactive analysis comparing the efficacy of low dose (7.5–15 U/kg/2 weeks) and high dose (40 U/kg/2 weeks) imiglucerase therapy for Chinese patients in response to the 2009 ERT shortage. Measuring blood counts, organ volumes, and bone syndromes, this study found no dose-dependent differences in visceral enlargement or anemia. While 20 U/kg/2 weeks was considered adequate to reverse organomegaly and cytopenia, it was less effective for patients with skeletal involvement [79]. Additionally, a report on two pediatric patients with GD3 [80] found that despite long-term, high-dose ERT, the patients developed avascular necrosis, which was also reported in previous studies of rare treated adults with GD1 [81,82]. In these cases, no relationship was found between the development of the bone infarction and ERT dose and duration, highlighting a limitation in the current ERT treatment, specifically in targeting certain tissues such as bone, which may not effectively take up the exogenous enzyme [80].
Glucocerebrosidase as a therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2020
Yu Chen, Richard Sam, Pankaj Sharma, Lu Chen, Jenny Do, Ellen Sidransky
After several decades of preclinical work, the first effective therapy for Gaucher disease, enzyme replacement therapy (ERT) became available in 1991 [15]. While initially a placental derived product, a recombinant form of the enzyme, imiglucerase was soon developed, and currently there are several approved forms of the recombinant enzyme. Each successfully reverses the anemia, thrombocytopenia and hepatosplenomegaly associated with Gaucher disease, remarkably improving the current clinical course for patients with Gaucher disease. However, ERT is a treatment, but not a cure, and it requires regular intravenous infusions of the costly enzyme. Furthermore, it does not cross the blood-brain -barrier (BBB), and thus is not effective in treating manifestations specifically encountered in patients with neuronopathic forms of the disease. A second therapeutic approach is substrate reduction therapy (SRT) targeting glucosylceramide synthesis, which also effectively reduces non-neurologic manifestations of Gaucher disease. However, since both ERT and SRT are extremely expensive and do not reverse neuronopathic Gaucher disease, there remains a strong rationale for developing new therapeutic strategies for patients with Gaucher disease.
Pharmacological treatment of pediatric Gaucher disease
Published in Expert Review of Clinical Pharmacology, 2018
Punita Gupta, Gregory Pastores
Based on the ICGG experience, benchmarking of ‘therapeutic goals’ was introduced [64] whereby one could assess individual patients’ progress relative to that of historical ICGG experience. The following are the criteria for therapeutic goals as formulated by a panel of experts in 2004 [55]. For hepatosplenomegaly, the goal is to reduce and maintain liver volume 1–1.5 times normal (by 3–5 years) and reduce and maintain spleen volume 2–8 times normal (by 2-5 years). For anemic and thrombocytopenic patients, respectively, hemoglobin >11 g/dl for women/children and >12 g/dl for men; platelet counts in patients with intact spleen and depending on baseline value, 1.5–2.0 fold-increase or doubling by 2–5 years of ERT [55]. These ‘goals’ also imply that other enzymes/treatment modalities would be required to show a lack of inferiority relative to imiglucerase-induced improvements. Thus, the achievements seen with imiglucerase are ‘benchmarks’ for therapy [65].