In Gaucher disease (GD), genetic deficiency of acid β-glucosidase leads to accumulation of its substrate glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Lipid-laden cells, most prominently seen as macrophages engorged with GlcCer and GlcSph-laden lysosomes, trigger chronic metabolic inflammation and multisystemic phenotypes. Among the pleiotropic effects of inflammatory cascades, the induction of glucosylceramide synthase accentuates the primary metabolic defect. First-line therapies for adults with GD type 1 include Enzyme Replacement Therapy (ERT) and eliglustat Substrate Reduction Therapy (SRT). The ENCORE phase 3 clinical trial of eliglustat demonstrated non-inferiority compared to ERT. It is not known whether switching stable patients from long-term ERT to SRT results in the incremental reversal of the disease phenotype and its surrogate indicators. Herein, we report real-world experience from a single tertiary referral center of 38 adult GD type 1 patients, stable on long-term ERT (mean 13.3 years), who switched to eliglustat SRT (mean 3.1 years). After switch to SRT, there was significant reduction in spleen volume (P = 0.003) while liver volume, which was normal at baseline, remained unchanged. Platelet counts increased significantly (P = 0.026). Concomitantly, there was reduction of three validated biomarkers of Gaucher disease activity: plasma GlcSph decreased from 63.7 ng/ml (95% CI, 37.6-89.8) to 26.1 ng/ml (95% CI, 15.7-36.6) (P < 0.0001); chitotriosidase fell from 1136.6 nmol/ml/h (95% CI, 144.7-2128.6) to 466.9 nmol/ml/h (95% CI, 209.9-723.9) (P = 0.002); and glycoprotein non-metastatic melanoma B (gpNMB) decreased from 59.3 ng/ml (95% CI, 39.7-78.9) to 43.6 ng/ml (95% CI, 30.7-56.6) (P = 0.0006). There were no episodes of avascular necrosis or fractures in patients on SRT. Patients reported favorable experiences of switching from alternate week infusions to oral therapy. Collectively, these results demonstrate that the switch to eliglustat SRT from ERT leads to incremental response, even in stable patients after long-term ERT.

在戈谢病 (GD) 中，酸性 β-葡萄糖苷酶的遗传缺陷导致其底物葡萄糖神经酰胺 (GlcCer) 和葡萄糖基鞘氨醇 (GlcSph) 的积累。载脂细胞，最显着地被视为充满 GlcCer 和 GlcSph 溶酶体的巨噬细胞，引发慢性代谢性炎症和多系统表型。在炎症级联反应的多效性中，葡萄糖神经酰胺合酶的诱导加剧了主要的代谢缺陷。成人 1 型 GD 的一线疗法包括酶替代疗法 (ERT) 和 eliglustat 底物还原疗法 (SRT)。与 ERT 相比，eliglustat 的 ENCORE 3 期临床试验证明了非劣效性。尚不清楚将稳定的患者从长期 ERT 转换为 SRT 是否会导致疾病表型及其替代指标的逐步逆转。在此，我们报告了来自一个三级转诊中心的 38 名成年 GD 1 型患者的真实世界经验，这些患者长期 ERT 稳定（平均 13.3 年），转为 eliglustat SRT（平均 3.1 年）。改用 SRT 后，脾脏体积显着减少（P  = 0.003），而基线时正常的肝脏体积保持不变。血小板计数显着增加 ( P  = 0.026)。同时，戈谢病活动的三个经过验证的生物标志物减少：血浆 GlcSph 从 63.7 ng/ml（95% CI，37.6-89.8）降至 26.1 ng/ml（95% CI，15.7-36.6）（P < 0.0001  ） ; 壳三糖苷酶从 1136.6 nmol/ml/h (95% CI, 144.7-2128.6) 下降到 466.9 nmol/ml/h (95% CI, 209.9-723.9) ( P  = 0.002)；和糖蛋白非转移性黑色素瘤 B (gpNMB) 从 59.3 ng/ml (95% CI, 39.7-78.9) 下降到 43.6 ng/ml (95% CI, 30.7-56.6) ( P = 0.0006）。接受 SRT 的患者没有发生缺血性坏死或骨折。患者报告了从隔周输液转为口服治疗的良好体验。总的来说，这些结果表明，即使在长期 ERT 后稳定的患者中，从 ERT 转换为 eliglustat SRT 也会导致反应增加。