Non-targeted siRNAs suppress blood and lymphatic vessel growth in vivo as effectively as siRNAs directed against a key angiogenic growth factor as a result of immune response activation rather than an RNAi effect, researchers reported today.
These data, appearing in the Proceedings of the National Academy of Sciences, suggest that siRNAs inhibit both hemangiogenesis and lymphangiogenesis regardless of their sequence or targets, raising concerns over the possibility of unintended effects with certain RNAi drugs, the investigators add.
"Collectively, our findings reveal a new facet of the unintended effects of siRNA," the team, led by the University of Kentucky's Jayakrishna Ambati, writes. And while these effects "could be harnessed for therapeutic advantage in angiogenesis-driven diseases … [they] should be carefully monitored in ongoing clinical trials of [siRNA-based] drugs in non-angiogenic diseases."
Still, Ambati stresses that his research should not be interpreted as evidence that siRNA-based therapeutics won't be successful.
"There are workarounds" to overcoming TLR3 activation, the simplest being the use of duplexes shorter than 21 nucleotides, he says. "It is not like [TLR3 activation] is some sort of impenetrable barrier."
The findings in PNAS build upon research Ambati and colleagues published about a year ago in Nature demonstrating that siRNAs that are 21 nucleotides in length or longer suppress neovascularization, regardless of their sequences or targets, by triggering the double-stranded RNA immune receptor toll-like receptor 3.
For the PNAS study, the investigators sought to "further explore this newly defined intersection between angiogenesis and innate immunity." Specifically, they set out to determine whether "the generic antihemangiogenic effects of siRNAs extended to other well-established and clinically relevant mouse models of neovascularization in response to corneal suture injury or hindlimb ischemia, and whether siRNA-mediated TLR3 activation also suppressed lymphangiogenesis," they write in the paper.
Alnylam Pharmaceuticals has initiated a phase I study of its siRNA-based liver cancer therapy ALN-VSP. The study will evaluate the drug's safety, tolerability, pharmacokinetics, and pharmacodynamics in about 55 patients with advanced liver cancers.
Genesis Research and Development, a New Zealand-based RNAi drug developer, has warned its investors that it may not secure the funding it needs to continue operations. Genesis has also not been able to recoup the NZ$2 million (USD$1.2 million) it is owed by the biofuels company Pure Power Global.
Targeted Genetics announced that it has not been able to raise the capital it may need to advance its drug development programs. It has enough funds to cover planned operations though the first half of this year.
Amount of series B funding that Traversa secured.
ADAM 17 and Glioma-Tumor Progression and Treatment
Grantee: Feng Jiang, Henry Ford Health System
Began: Jan. 1, 2009; Ends Dec. 31, 2013
Jiang will be examining a tumor necrosis factor converting enzyme, called ADAM 17, that fosters glioma multiforme invasion to determine if inhibiting the enzyme will reduce tumor growth. To do so, Jiang will be using in vitro and in vivo models of glioma and a variety of methods, ranging from siRNA to laser capture confocal microscopy and MRI.
Structure and Mechanism of the RISC-loading Complex
Grantee: Ian John MacRae, Scripps Research Institute
Began: Dec. 1, 2008; Ends Nov. 30, 2013
With this grant, MacRae will be examining the RISC-loading complex that is part of the miRNA assembly pathway. With both biochemistry and structural biology techniques, he plans to "focus on dissecting the mechanisms underlying miRNA recognition and processing efficiency" to better understand the miRNA process.