Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.
Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.
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DOI：
10.1186/s12967-023-03903-3
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发表时间：
2023-02-14
影响因子：
7.4
通讯作者：
Izrael, Michal
中科院分区：
文献类型：
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作者：
Gotkine, Marc;Caraco, Yoseph;Lerner, Yossef;Blotnick, Simcha;Wanounou, Maor;Slutsky, Shalom Guy;Chebath, Judith;Kuperstein, Graciela;Estrin, Elena;Ben-Hur, Tamir;Hasson, Arik;Molakandov, Kfir;Sonnenfeld, Tehila;Stark, Yafit;Revel, Ariel;Revel, Michel;Izrael, Michal
星形胶质细胞功能障碍是ALS的病理因素之一。因此，鞘内注射ALS中健康的星形胶质细胞可以潜在地补偿病变的星形胶质细胞。AstroRx®是一种基于同种异体细胞的产品，由来自胚胎干细胞的健康和功能正常的人类星形胶质细胞组成。AstroRx®被证明可以清除过量的谷氨酸，减少氧化应激，分泌各种神经保护因子，并发挥免疫调节剂的作用。向ALS动物模型鞘内注射AstroRx®可减缓疾病进展并延长生存期。在这里，我们报告了一项首次人类临床研究的结果，该研究评估了鞘内注射AstroRx®治疗ALS患者的效果。我们进行了一项I/IIa期、开放标签、剂量递增的临床试验，以评估鞘内注射AstroRx®治疗ALS患者的安全性、耐受性和疗效。5例患者鞘内注射100 × 106AstroRx®细胞，5例患者鞘内注射250 × 106细胞(分别为低剂量和高剂量)。分别在治疗前3个月(磨合期)和治疗后12个月(随访期)记录安全性和有效性评估。单次服用AstroRx®无论是低剂量还是高剂量都是安全和耐受性良好的。没有与AstroRx®本身相关的不良事件(AEs)报告。与鞘内(IT)手术相关的一过性AEs均为轻至中度。研究表明，通过ALSFRS-R治疗前的斜率变化来衡量，在治疗后的前3个月内保持了一种临床上有意义的效果。在100 × 106 AstroRx®ARM中，ALSFRS-R恶化速度在治疗后的前3个月从治疗前的−=0.88/月减弱到−=0.30/月(p = 0.039)。在250 × 106 AstroRx®ARM中，ALSFRS-R斜率从−的1.43/月降至−的0.78/月(p = 0.0023)。在由5名患者组成的快速进展型亚组中，这种影响甚至更加深刻。使用手持测力仪测量的肌肉力量在统计学上没有显著变化，缓慢的肺活量在研究期间继续恶化。总体而言，这些发现表明，对肌萎缩侧索硬化症患者单一IT应用AstroRx®100 × 106或250 × 106细胞是安全的。在细胞注射后的前3个月观察到了有益的临床效果的信号。这些结果支持对AstroRx®鞘内重复给药的进一步调查，例如每3个月一次。试用登记：NCT03482050。网上版载有补充材料，可在10.1186/s12967-023-03903-3查阅。
Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from − 0.88/month pre-treatment to − 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from − 1.43/month to − 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. Trial Registration: NCT03482050. The online version contains supplementary material available at 10.1186/s12967-023-03903-3.
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DOI：
10.1080/21678421.2017.1421666
发表时间：
2018-01-01
影响因子：
2.8
作者：
Fournier, Christina N.;Schoenfeld, David;Glass, Jonathan D.
通讯作者：
Glass, Jonathan D.
影响因子：
6.2
作者：
Fasciani, Ilaria;Pluta, Paula;Barrio, Luis C.
通讯作者：
Barrio, Luis C.
影响因子：
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作者：
APPEL, SH;STEWART, SS;BELENDIUK, GW
通讯作者：
BELENDIUK, GW
重新审视CNS免疫特权的机制。
影响因子：
16.8
作者：
Louveau A;Harris TH;Kipnis J
通讯作者：
Kipnis J
DOI：
10.1056/nejmoa1916945
发表时间：
2020-09-03
期刊：
The New England journal of medicine
影响因子：
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作者：
通讯作者：
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