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.

GRN 突变导致颗粒体蛋白前体单倍体不足，最终导致额颞叶痴呆 (FTD-GRN)。 PR006 是一种研究性基因疗法，使用腺相关病毒血清型 9 (AAV9) 载体传递颗粒蛋白基因 ( GRN )。在非临床研究中，PR006 转导源自 FTD-GRN 患者诱导多能干细胞的神经元，导致 Grn 敲除小鼠中颗粒体蛋白前体表达并改善脂褐质、溶酶体和神经炎症病理学，并且除了极少的无症状症状外，PR006 具有良好的耐受性非人类灵长类动物的背根神经节病。我们启动了首次人体 1/2 期开放标签试验。在此，我们报告了低剂量队列中最后一位接受治疗的患者 ( n  = 6) 达到 12 个月随访时间点时触发的预先指定的中期分析结果。我们还包括来自中等剂量队列的初步数据（n  = 7）。主要终点是安全性、免疫原性以及脑脊液（CSF）和血液中颗粒体蛋白前体水平的变化。次要终点是临床痴呆评级 (CDR) 加上国家阿尔茨海默病协调中心 (NACC) 额颞叶变性 (FTLD) 评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均产生了治疗引起的抗 AAV9 抗体，但没有一人产生抗颗粒体蛋白前体抗体。脑脊液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。三名患者出现深静脉血栓。治疗后 18 个月发生 1 例死亡（无关）。所有患者在 PR006 治疗后脑脊液颗粒体蛋白前体均增加；大多数患者的血液颗粒体蛋白前体增加，但只是短暂的。 PR006 治疗后 NfL 水平短暂升高，可能反映了背根神经节毒性。根据 CDR 量表，进展率处于 FTD 患者报告的广泛范围内。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研究来确认 PR006 的安全性和潜在功效。 ClinicalTrials.gov 标识符：NCT04408625。