Collaboration eyes systemic RNAi delivery
to selectively switch off genes associated with disease has
captured the attention of drug developers, but as with antisense
before it, delivering the agents is the main obstacle.
And just like antisense, the first drug to enter trials based on double-stranded RNA (dsRNA) sequences - from Acuity Pharmaceuticals - is for an eye disease. This simplifies dosing because the candidate can be delivered by a relatively simple injection into the eyeball.
Delivering nucleic acid-based drugs successfully to internal tissues is a tougher challenge, and one which a collaboration between US company Nucleonics and German drug delivery specialist Novosom hopes to overcome.
RNAi relies on the use of short nucleic acid sequences that bind to and inactivate the machinery in the cell that leads to protein transcription - a process known as post-transcriptional gene silencing.
Nucleonics focuses on the development of expressed RNA interference-based (eiRNA) therapeutics, a variation on the technology whereby plasmid DNA coding for relevant dsRNA is inserted into targeted cells, letting the cells produce and deliver the sequences themselves. Cellular mechanisms then cleave the dsRNA into specifically encoded siRNAs (short interfering RNA), which silence the targeted genes.
Meanwhile, Novosom has developed a formulation technology under the Smarticles banner that has been shown to deliver nucleic acid sequences into cells effectively. The two companies hope to combine their resources to develop new treatments for the liver diseases hepatitis B and C.
"Delivering DNA to cells presents a considerable challenge, and Novosom has demonstrated that they can deliver DNA and other nucleic acids to liver cells with great efficiency," said Dr C Satishchandran, Nucleonics' co-founder and senior vice president, research and development.
Novosom's technology is based on lipid particles (liposomes), a vehicle used to deliver drugs with poor bioavailability - such as the antifungal amphotericin B and cancer drug doxorubicin - for many years.
Like conventional liposomes, Novosom's Smarticles are stable in blood and distribute in the same manner, but they have one fundamental difference. They become positively charged when they cross cell membranes, leading to effective delivery of their cargo within cells. The liver and spleen, along with sites of inflammation and tumours, are primary targets for the charged liposomes.
For Nucleonics, Novosom's technology will be used in a second-generation product, as it already has a lead drug candidate for hep B in the build-up to clinical trials that is based on an in-house delivery system. But Dr Satishchandran believes Novosom's approach is potentially more efficient.
Nucleonics has taken an option to exclusively license and commercialise Novosom's delivery technology for Nucleonics' eiRNA therapeutics for hep B and C, but financial terms of the agreement were not disclosed.
