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Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Of the three types of Niemann-Pick disease (NPD, sphingolipidoses), mutations in the SMPD1 gene encoding acid sphingomyelinase (ASM) are responsible for NPD type A and Type B, and only type A is associated with neuronal degeneration in the CNS; ASM hydrolyzes sphingomyelin to ceramide and phosphocholine (see the following scheme), essential components of myelin in neurons. Patients with NPD type A have a low life expectancy, whereas those with type B NPD can reach adulthood due to a higher residual activity of ASM; however, as characteristic for other storage diseases, organs such as liver, spleen, and at a later state the lung of NPD patients are affected. Zhou et al. (2016) solved the structure of human ASM holoenzyme; they found that the catalytic domain has a metallophosphatase fold with two zinc ions that activate a water molecule for nucleophilic attack of the phosphodiester bond. A mapping of known mutations contributed to an understanding between enzyme dysfunction and phenotypes observed in ASMD patients. In 2015, Genzyme Corporation, a Sanofi company presented the positive results of an open-label, multicenter, ascending-repeat-dose study of the tolerability and safety of recombinant human acid sphingomyelinase (rhASM; olipudase alfa) in Niemann-Pick disease type B patients. The study was performed with five patients. McGovern et al. (2016) reported about another study with 11 patients according to which no serious adverse drug reactions (ADRs) occurred; they came to the conclusion that the maximum tolerated dose of olipudase alfa in adults with NPD type B is 0.6 mg/kg. In addition, an enhanced delivery and effects of ASM by ICAM-1 (a protein overexpressed during inflammation)-targeted nanocarriers in NPD type B mice was observed by Garnacho et al. (2017). The use of polystyrene and poly(lactic-co-glycolic acid) nanocarriers enabled increased absolute enzyme delivery to lung, liver, and spleen, over the naked enzyme.
Ceramide pathway: A novel approach to cancer chemotherapy
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Mahdi Mashhadi Akbar Boojar, Masoud Mashhadi Akbar Boojar, Sepide Golmohammad
The acidic form of sphingomyelinase is one of the most important isoforms of this lysosomal enzyme that performs the degradation and conversion of cytoplasmic membrane sphingomyelin to ceramide [26]. Therefore, its strengthening has become a target for anti-tumor drugs. The neutral and alkaline isoforms of sphingomyelinase are mainly present in the cytoplasm and are often magnesium and zinc-dependent, and the abundance of these heavy metals is also a factor in the enhancement of these enzymatic systems [33]. Suppression of this pathway in cancer cells has been introduced as a resistance mechanism to some chemotherapy agents [26].