A new brain‐penetrant glucosylceramide synthase inhibitor as potential Therapeutics for Gaucher disease

Abstract

Gaucher disease (GD), one of the most prevalent lysosomal storage disorders (LSDs), is caused by mutations in the GBA gene which encodes glucocerebrosidase. Glycosphingolipids (GSLs) such as glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) are substrates of glucocerebrosidase, and GD is characterized by the pathological accumulation of these GSLs. Clinical features of GD include anemia, thrombocytopenia, enlargement of the liver and spleen and bone dysplasia. Additionally, there are cases showing neurological symptoms such as seizures, cognitive impairment, ataxia, and lack of coordination, categorized into GD type 2 or 3 in distinction from type 1, nonneuropathic GD (Alaei et al., 2019). GlcSph in plasma increases and is considered a biomarker for GD progression (Dekker et al., 2011;Rolfs et al., 2013). The level of GlcSph in the brain is elevated in GD type 2 and 3 patients but not in type 1 (Nilsson & Svennerholm, 1982;Orvisky et al., 2002). Therefore, GlcSph accumulation in the brain could be a key driver of the pathogenesis of neuropathic GD. In fact, the neurotoxic effect of GlcSph, such as induced apoptosis, has been reported in in vitro studies (Schueler et al., 2003;Sueyoshi et al., 2001).Therapeutic approaches, such as enzyme replacement therapy using recombinant glucocerebrosidase and substrate reduction therapy using miglustat (Cox et al., 2003) or eliglustat (Smid &

Newborn screening for Gaucher disease in Japan

“…HSCT has been shown to be effective for neurological symptoms in some cases but the evidence is insufficient [ 38 ]. Currently, medical therapies, including ERT and SRT, that can cross the BBB [ 39 , 40 ], pharmacological chaperone therapy [ 41 ], and gene therapy [ 42 ] are under development as potential treatments for neurological symptoms. The usefulness of NBS for GD can be enhanced by the successful application of these treatments.…”

Targeting the Sphingolipid Rheostat in Gliomas

“…However, some effects of D-PDMP are not attributed to its UGCG inhibition, and additional experimentation is required to elucidate the other mechanisms of action [ 172 ]. Other novel brain-penetrant drugs, such as T-036, have recently been discovered and require additional investigation to determine their capacity for inhibiting cancer growth [ 173 ].…”

Juvenile Mucopolysaccharidosis plus disease caused by a missense mutation inVPS33A

“…Moreover, should substrate reduction with eliglustat (Shayman, 2015;Cox, 2010;McEachern, 2007) ameliorate the systemic disease, an opportune case for using brain-penetrant analogues (Marshall, 2016;Fujii, 2021) to address the neurodegenerative manifestations of the MPS plus would be greatly strengthened.…”

“…Each treatment substantially improved defective intracellular trafficking of glycosphingolipids and thus offer a potential therapeutic opportunity in this lethal orphan disease (Pavlova, 2019) [3]. Moreover, should substrate reduction with eliglustat (Shayman, 2015; Cox, 2010; McEachern, 2007) ameliorate the systemic disease, an opportune case for using brain-penetrant analogues (Marshall, 2016; Fujii, 2021) to address the neurodegenerative manifestations of the MPS plus would be greatly strengthened.…”