美国斯坦福大学医学院M. Peter Marinkovic小组报道了体内局部基因治疗隐性营养不良型大疱性表皮松解症(RDEB)的1期和2期临床试验结果。该项研究成果发表在2022年3月28日出版的《自然-医学》上。

研究人员评估了beremagene geperpavec (B-VEC) 治疗RDEB的效果，B-VEC是一种工程化、由1型单纯疱疹病毒(HSV-1)载体递送非复制COL7A1的细胞治疗方法。B-VEC恢复了RDEB角质形成细胞、成纤维细胞、RDEB小鼠和人RDEB异种移植物中C7的表达。随后，一项随机、安慰剂对照的1期和2期临床试验 (NCT03536143) 评估了9名RDEB患者在12周内反复接受局部B-VEC或安慰剂治疗后的伤口愈合情况。未发现2级或以上B-VEC相关不良事件或载体脱落或与组织结合处的皮肤免疫反应。HSV-1和锚定原纤维成分胶原VII (C7)抗体的表达在基线水平或在B-VEC治疗后增加，而对安全性或有效性没有明显影响。

C7表达、锚定原纤维组装、伤口表面积减少、伤口闭合持续时间和B-VEC治疗后伤口闭合时间的主要和次要目标均得到满足。鉴于治疗的伤口比例很小，因此未评估患者报告的疼痛严重程度这一次要结果。由于其他终点存在冗余，未对全部次要终点进行评估。该研究表明，B-VEC是一种易于给药、安全耐受的局部分子矫正疗法，可促进RDEB患者的伤口愈合。

据了解，RDEB是一种终生遗传性皮肤病，由COL7A1突变引起的水疱、创伤和瘢痕形成，该基因编码C7。

附：英文原文

Title: In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial

Author: Gurevich, Irina, Agarwal, Pooja, Zhang, PeiPei, Dolorito, John A., Oliver, Stacie, Liu, Henry, Reitze, Nicholas, Sarma, Nikhil, Bagci, Isin Sinem, Sridhar, Kunju, Kakarla, Visesha, Yenamandra, Vamsi K., OMalley, Mark, Prisco, Marco, Tufa, Sara F., Keene, Douglas R., South, Andrew P., Krishnan, Suma M., Marinkovich, M. Peter

Issue&Volume: 2022-03-28

Abstract: Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain–severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

DOI: 10.1038/s41591-022-01737-y

Source: https://www.nature.com/articles/s41591-022-01737-y