Clinical Response and Corresponding Blood Transcriptome Pathways Pre- And Post-Treatment Of Hereditary Angioedema Prodromes Compared To Active Swelling Attacks.

Abstract

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.