RNAi Therapy Takes Step from Bench to Bedside

RNA interference (RNAi) is a Nobel Prize-winning discovery first published in 1998 by Andrew Fire and Craig Mello. The potential of RNAi technology to silence genes involved in disease was apparent from the beginning, at least in theory. These theoretical RNAi therapies would switch off genes upregulated in diseased cells, such as in cancer or Huntington’s disease. However, delivering RNAi treatments to deep tissues within the body posed enormous challenges until now.

tumor-vegfRNAi is an ancient mechanism conserved through evolution in almost all eukaryotes—organisms whose cells have a nucleus—that can “silence” a specific gene, that is, turn off messenger RNA (mRNA) carrying instructions transcribed from DNA. Eurkaryotes use RNAi as a key tool in remodeling tissue during development and as a first line defense against invading viruses. RNAi involves very short molecules of double-stranded RNA (siRNA). One strand finds its exact complement of nucleotide sequences in the targeted mRNA, binds to it, and steers it into an RNA-induced silencing complex (RISC) where it is cleaved into silence. The beauty of RNAi is its specificity. To the delight of research biologists, RNAi can be used to silence every single gene, one by one, in an organism’s genome. But while RNAi has become a powerful research tool, it has not been successfully utilized in the clinic to treat diseases.

Now comes a report of a clinical trial in the journal Cancer Discovery by an international group of collaborators examining the activity and safety of an RNAi approach to cancer treatment. A crucial missing element in RNAi research for clinical applications has been the lack of a safe delivery method. The experimental candidates all involved viral vector systems. But viral vectors pose safety concerns, so researchers have been seeking nonviral delivery methods such as lipid-based or polymeric vectors. This new report describes the use of lipid nanoparticles (LNPs), formulated to deliver siRNA in humans. This is the first reported study in humans using LNP-formulated siRNAs to treat disease.

This Phase I study employed a LNP formulation of siRNAs targeting vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP) in advanced cancer patients with liver involvement. Blocking VEGF would undermine the ability of cancer cells to spread. Targeting KSP, a driver of cell division (mitosis), could induce cell cycle arrest and ultimately cell death in tumors.

The researchers say that their RNAi-mediated therapy demonstrated mRNA cleavage in liver, on-target pharmacodynamic effects in liver metastases, and the ability to measure drug in hepatic and extrahepatic tumor biopsies, as well as antitumor activity at both hepatic and extrahepatic sites of disease. This study could have important implications for future RNAi-based drug development in oncology by showing specific multitargeting, a safe delivery method, and a new array of druggable targets.

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