RATIONALE Approximately 85% Hereditary angioedema (HAE) attacks are associated with prodromal symptoms. We investigated the clinical effect of treating HAE-C1 inhibitor (HAE-C1INH) Type 1 patients with Conestat Alfa® (recombinant human C1-INH) during their prodrome versus an active swelling episode and associated changes in blood transcriptomic genes and pathways pre- vs. post-treatment. METHODS A two-center, unblinded, case-crossover study randomly assigned HAE-C1INH Type 1 patients (N=5) to prodrome or attack-treatment groups; after a patient was treated for either two prodromes or two HAE attacks they were crossed-over to be treated for two HAE attacks or two prodromes. All patients were treated during the prodrome or acute attack with Conestat Alfa® (50 IU/kg body wt., max. 4200 IU for body weight ≥85kg). Blood samples for analysis by RNAseq were obtained at (i) baseline and (ii) during the prodrome before and after treatment and (iii) during an attack before and after treatment. Differentially regulated genes and pathways were elucidated by Ingenuity Pathway Analysis (IPA, Qiagen). RESULTS Treatment during the HAE prodrome with Conestat Alfa® was as effective at preventing progression to a swelling episode as treatment of an acute attack. HAE prodromes were associated with upregulation of multiple inflammatory extracellular matrix genes, neuropeptide, and inflammasome member genes (e.g., SPARCL1, AGRP, NLRP9; log FC = 4.1, 3.9 and 3.0, respectively). TNF-a and IL-10 were two major hub genes in prodrome-associated enriched gene networks. Conestat Alfa® treatment resulted in reversal of the disease signature in HAE-associated dysregulated pathways. Approximately 42% of prodrome-associated Differentially Expressed Genes (DEGs) were also associated with HAE attacks. The enriched gene networks with hub genes for prodrome (ERK and VEGF) and for acute attack (Insulin and SERPINA1) stages of HAE were identified. The major enriched pathways shared between HAE prodrome and attack were associated with neutrophil function and prostaglandin metabolism. CONCLUSION Treatment of HAE-C1INH Type 1 patients who have a well-defined prodrome that historically results in an acute attack may be justified clinically and mechanistically. This approach would represent a paradigm shift for management of HAE on-demand treatment.

中文翻译：

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与活动性肿胀发作相比，遗传性血管性水肿前驱症状治疗前后的临床反应和相应的血液转录组途径。


基本原理 大约 85% 的遗传性血管性水肿 （HAE） 发作与前驱症状有关。我们研究了用 Conestat Alfa®（重组人 C1-INH）治疗 HAE-C1 抑制剂 （HAE-C1INH） 1 型患者前驱症状与活动性肿胀发作期间的临床效果，以及治疗前后血液转录组基因和通路的相关变化。方法 一项双中心、非盲、病例交叉研究将 HAE-C1INH 1 型患者 （N=5） 随机分配到前驱组或发作治疗组;在患者接受 2 次前驱症状或 2 次 HAE 发作治疗后，他们被交叉接受 2 次 HAE 发作或 2 次前驱症状的治疗。所有患者在前驱或急性发作期间均使用 Conestat Alfa® （50 IU/kg 体重，体重 ≥85 kg） 最大 4200 IU 进行治疗。用于 RNAseq 分析的血样是在 （i） 基线和 （ii） 治疗前后的前驱期间以及 （iii） 治疗前后发作期间获得的。通过 Ingenuity Pathway Analysis （IPA， Qiagen） 阐明差异调控的基因和通路。结果 在 HAE 前驱症状期间使用 Conestat Alfa® 进行治疗在防止进展为肿胀发作方面与治疗急性发作一样有效。HAE 前驱症状与多个炎性细胞外基质基因、神经肽和炎性小体成员基因 （例如，SPARCL1、AGRP、NLRP9;log FC = 4.1、3.9 和 3.0 的上调有关。TNF-a 和 IL-10 是前驱症状相关富集基因网络中的两个主要枢纽基因。Conestat Alfa® 治疗导致 HAE 相关失调通路中的疾病特征逆转。大约 42% 的前驱相关差异表达基因 （DEG） 也与 HAE 发作有关。 确定了具有 HAE 前驱期 （ERK 和 VEGF） 和急性发作 （胰岛素和 SERPINA1） 期枢纽基因的富集基因网络。HAE 前驱症状和发作之间共享的主要富集途径与中性粒细胞功能和前列腺素代谢有关。结论 对于具有明确前驱症状且历史上导致急性发作的 HAE-C1INH 1 型患者的治疗可能在临床和机制上是合理的。这种方法将代表 HAE 按需治疗管理的范式转变。