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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02973-0

摘要内容如下：

GRN突变导致颗粒蛋白前体单倍体不足，最终导致额颞痴呆（FTD-GRN）。PR006是一种使用腺相关病毒血清型9（AAV9）载体递送颗粒体蛋白基因（GRN）的试验性基因疗法。在非临床研究中，PR006转导的神经元来源于FTD-GRN患者的诱导多能干细胞，导致GRN基因敲除小鼠的颗粒蛋白前体表达和脂褐素、溶酶体和神经炎症病理的改善，并且除非人灵长类动物的轻微、无症状背根神经节病外，耐受性良好。我们启动了首次人体1/2期开放标签试验。在此，我们报告了一项预先指定的中期分析的结果，该分析是由低剂量队列（n=6）中最后一名接受治疗的患者达到12个月的随访时间点而触发的。我们还纳入了来自中等剂量队列（n=7）的初步数据。主要终点是安全性、免疫原性以及脑脊液（CSF）和血液中颗粒蛋白前体水平的变化。次要终点是临床痴呆等级（CDR）加上国家阿尔茨海默病协调中心（NACC）额颞叶变性（FTLD）等级量表和神经丝轻链（NFL）水平。将PR006一次性注入小脑延髓池通常是安全的，且耐受性良好。所有患者的脑脊液中都出现了治疗中出现的抗AAV9抗体，但没有出现抗颗粒蛋白前体抗体。CSF白细胞增多是最常见的PR006相关不良事件。发生了12起严重不良事件，大部分与PR006无关。3例患者发生深静脉血栓形成。治疗后18个月有1例死亡（无关）。PR006治疗后，所有患者的CSF颗粒蛋白前体均升高；大多数患者血中颗粒蛋白前体升高，但仅为一过性升高。PR006治疗后NFL水平短暂升高，可能反映了背根神经节毒性。基于CDR量表的进展率在报告的FTD患者的广泛范围内。这些数据为PR006的安全性和生物活性提供了初步见解。需要更长时间的随访和更多的研究来证实PR006的安全性和潜在疗效。ClinicalTrials.gov标识符：NCT04408625。

英文原文如下：

Abstracts

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

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