Enhancing Efficacy and Safety of ARO-HIF2 RNAi Therapy for Clear Cell Renal Carcinoma

The research focuses on the development of a therapeutic approach for clear cell renal cell carcinoma (ccRCC), a cancer type often linked to the inactivation of the VHL tumor suppressor gene. The absence of VHL leads to an increase in hypoxia-inducible factors (HIFs), with HIF2α being a significant promoter of ccRCC. Arrowhead Pharmaceuticals has created an RNA interference therapy, HIF2 RNAi, designed to specifically target and reduce HIF2α expression. This therapy utilizes the company's proprietary TRiM delivery system, which includes a potent RNAi trigger, targeting ligands for delivery, and enhancements for better pharmacokinetics.

In the study, the effectiveness of the HIF2 RNAi therapy was assessed using an orthotopic ccRCC tumor xenograft model with A498 ccRCC cells. The treatment was administered intravenously, and gene silencing was measured through qRT-PCR after isolating tumor RNA. The results showed that for substantial HIF2α mRNA knockdown, the therapy needed to be optimized with pharmacokinetic enhancements and tumor targeting ligands. The optimized HIF2 RNAi construct showed a 10-fold increase in potency, and a loading dose regimen was more effective than a single dose. The therapy led to an 85% knockdown of HIF2α mRNA, inhibiting tumor growth and significantly improving survival rates in the xenograft model. The therapy also caused extensive tumor destruction, evident through histological analysis.

Further research indicated that loading doses could be given four hours apart without a loss of effectiveness, suggesting a one-day dosing regimen that could be more clinically feasible. The maximum knockdown of HIF2α mRNA was observed approximately seven days post-dosing and lasted about a week, indicating the potential for less frequent dosing in clinical settings. A preliminary toxicity study in rats suggested a broad safety margin for the treatment.

In conclusion, the TRiM delivery platform effectively delivers an RNAi therapeutic targeting HIF2α for ccRCC treatment, offering a new therapeutic strategy that could be used alone or in combination with other treatments to improve patient outcomes. The study was presented at the American Association for Cancer Research Annual Meeting in 2019.