scholarly journals Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective

2021 ◽  
Vol 22 (23) ◽  
pp. 12870
Author(s):  
Carolina Pinto ◽  
Diana Sousa ◽  
Vladimir Ghilas ◽  
Andrea Dardis ◽  
Maurizio Scarpa ◽  
...  
Keyword(s):  
Immune System ◽  
Enzyme Replacement Therapy ◽  
Lung Disease ◽  
Replacement Therapy ◽  
Foam Cell ◽  
Central Nervous System Involvement ◽  
Acid Sphingomyelinase ◽  
Pulmonary Insufficiency ◽  
Enzyme Replacement ◽  
Sphingomyelinase Deficiency

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of varying degrees of sphingomyelin. Lipid storage leads to foam cell infiltration in tissues, and clinical features including hepatosplenomegaly, pulmonary insufficiency and in some cases central nervous system involvement. ASM enzyme replacement therapy is currently in clinical trial being the first treatment addressing the underlying pathology of the disease. Therefore, presently, it is critical to better comprehend ASMD to improve its diagnose and monitoring. Lung disease, including recurrent pulmonary infections, are common in ASMD patients. Along with lung disease, several immune system alterations have been described both in patients and in ASMD animal models, thus highlighting the role of ASM enzyme in the immune system. In this review, we summarized the pivotal roles of ASM in several immune system cells namely on macrophages, Natural Killer (NK) cells, NKT cells, B cells and T cells. In addition, an overview of diagnose, monitoring and treatment of ASMD is provided highlighting the new enzyme replacement therapy available.

scholarly journals Clinical relevance of endpoints in clinical trials for acid sphingomyelinase deficiency enzyme replacement therapy

2020 ◽  
Vol 131 (1-2) ◽  
pp. 116-123
Author(s):  
Simon A. Jones ◽  
Margaret McGovern ◽  
Olivier Lidove ◽  
Roberto Giugliani ◽  
Pramod K. Mistry ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Clinical Relevance ◽  
Acid Sphingomyelinase ◽  
Enzyme Replacement ◽  
Sphingomyelinase Deficiency

scholarly journals One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency

2021 ◽  
Author(s):  
George A. Diaz ◽  
Simon A. Jones ◽  
Maurizio Scarpa ◽  
Karl Eugen Mengel ◽  
Roberto Giugliani ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Phase 1 ◽  
Lipid Profiles ◽  
Acid Sphingomyelinase ◽  
Open Label ◽  
Liver Transaminase ◽  
Enzyme Replacement ◽  
Sphingomyelinase Deficiency ◽  
One Year

Abstract Purpose To assess olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. Methods This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. Results Twenty patients were enrolled: four adolescents (12–17 years), nine children (6–11 years), and seven infants/early child (1–5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). Conclusion In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.

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