Safety Monitoring of Gene Therapy for Spinal Muscular Atrophy with Onasemnogene Abeparvovec -A Single Centre Experience.
Safety Monitoring of Gene Therapy for Spinal Muscular Atrophy with Onasemnogene Abeparvovec -A Single Centre Experience.
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DOI：
10.3233/jnd-200593
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发表时间：
2021
影响因子：
3.3
通讯作者：
Kirschner J
中科院分区：
文献类型：
--
作者：
Friese J;Geitmann S;Holzwarth D;Müller N;Sassen R;Baur U;Adler K;Kirschner J
最近，基因治疗onasemnogene abeparvovec已被批准用于治疗脊髓性肌萎缩症（SMA）。由于临床试验的经验有限，仍不确定该治疗对哪些患者人群安全有效。我们报告了我们在德国波恩大学医院连续8例SMA患者接受标准剂量奥那司明基因abeparvovec（1.1×1014 vg/kg）治疗的经验。所有患者在基因治疗前一天开始接受1 mg/kg/d泼尼松龙预防性免疫抑制4周。我们治疗了8名患者（4名男性，4名女性，年龄范围10-37个月），体重在7.1至11.9 kg之间。 所有患者均具有2或3个SMN 2基因拷贝，且既往接受过nusinersen治疗。在用onasemnogene abeparvovec治疗后，所有患者都表现出体温暂时升高和转氨酶水平升高。除一名患者外，所有患者都需要增加或延长标准类固醇剂量以控制免疫反应。在1例重度病例中，肝损伤与肝功能受损相关。该患者接受了5天的类固醇脉冲治疗。血细胞计数显示6/8例患者无症状性血小板减少（<150×109/L），基因治疗后单核细胞显著增加。在给药后观察期间，肝脏值和血细胞计数恢复至几乎正常水平。肌钙蛋白I在4/8例患者中升高超过正常限度，但与心脏评价的任何异常无关。在更广泛的患者中，使用onasemnogene abeparvovec治疗与更高的不良事件发生率相关。在我们的病例中，通过密切监测和调整免疫抑制方案可以控制免疫反应。需要进一步的研究来更好地了解基因治疗后的免疫反应，并理想地确定有更严重反应风险的患者。
Recently gene therapy with onasemnogene abeparvovec has been approved for the treatment of spinal muscular atrophy (SMA). As the experience from clinical trials is limited, there are still uncertainties for which patient population the treatment can be considered safe and effective. We report our experience with eight consecutive patients with SMA who were treated with the standard dose of onasemnogene abeparvovec (1.1×1014 vg/kg) at the University Hospital Bonn, Germany. All patients received prophylactic immunosuppression with 1 mg/kg/d prednisolone for four weeks starting on the day before gene therapy. We treated eight patients (4 male, 4 female, age range 10–37 months) with a body weight between 7.1 and 11.9 kg. All patients had 2 or 3 copies of the SMN2-gene and were previously treated with nusinersen. Following treatment with onasemnogene abeparvovec all patients showed a temporary increase of the body temperature and an increase of transaminase levels. In all but one patient it was necessary to increase or prolong the standard steroid dose to control the immune response. In one severe case, liver damage was associated with impaired liver function. This patient received a steroid pulse therapy for five days. Blood counts revealed asymptomatic thrombocytopenia (<150×109/L) in 6/8 patients and a significant increase of monocytes following gene therapy. Liver values and blood counts returned to almost normal levels during the post-treatment observation period. Troponin I increased above normal limit in 4/8 patients but was not associated with any abnormalities on cardiac evaluation. In a broader spectrum of patients, treatment with onasemnogene abeparvovec was associated with a higher rate of adverse events. In our cases it was possible to control the immune response by close monitoring and adaptation of the immunosuppressive regimen. Further research is needed to better understand the immune response following gene therapy and ideally to identify patients at risk for a more severe reaction.