Study Provides Insights into Masked RNAi Trigger Approach by Solstice Biologics

In early 2013, Solstice Biologics was the first most notable RNAi platform start-up after the industry had gone through the 2008-2011 RNAi Valley of Death.  The idea was to develop new single molecule RNAi triggers that would have better pharmacologic attributes than the highly negatively charged small double-stranded RNAs, as well as increased stability and reduced immunogenicity.

Today, a publication by the Dowdy group (Meade et al 2014), the academic birthplace of the technology, was published in Nature Biotechnology revealing for the first time more detailed insights into the fundamental approach.

Accordingly, the charge and stability issues have been addressed by esterifying the sugar-phosphate backbone with a biocleavable thioester, turning the phosphate diester into a triester.  Despite some steric constraints due to the nature of the double helix, the majority of phosphates could thus be triesterified thereby creating a more or less neutral RNAi trigger molecule: siRNNs (small interfering ribonucleic neutrals).

Once in the cytoplasm of the target cell, the triesterified RNAi triggers get converted by the ubiquitously expressed thioesterases into canonical charged RNAi triggers which only then become competent for utilization by the RNAi machinery.

Importantly, the molecules could be synthesized by methods closely related to standard phosphoramidite-based synthesis using modified phosphoramidites as the building blocks.  To this end, the Dowdy group and Solstice have created a library of modified phosphoramidites, including those amenable to the conjugation to cell-targeting ligands and endosomal release functionalities.

The study validated the high stability and reduced immunogenicity of the siRNNs and showed their increased binding affinity to plasma proteins such as albumins.  The latter is predicted to facilitate improved pharmacokinetics.  

Unfortunately, the in vivo validation stopped at the stage of using GalNAcs as the targeting ligand, because this attribute is predicted to be an advantage for particularly the delivery outside the liver where we might not find receptors with high uptake capacity similar to ASGPR on hepatocytes.

Another favorable attribute of the charge-neutral siRNNs, but which remains to be demonstrated, is improved tissue penetration.   Finally, it is possible that siRNNs have an advantage in overcoming cell membranes as well which is consistent with the apparent improved potency of GalNAc-siRNNs over standard siRNA-GalNAc conjugates (40 vs 55% knockdown in an experiment).

In many ways, siRNNs remind me of the self-delivering RNAi trigger approach first pioneered by Dharmacon and later adopted by RXi Pharmaceuticals.  However, there are at least two important differences: 1) self-delivering RNAi triggers still contain negative charge; and 2) self-delivering RNAi triggers should be structurally more flexible due to the shortened double-stranded region (~12 base-pairs vs 19 base-pairs) which, however, comes at the expense of impaired potency.

I greatly welcome this publication as it represents a fundamentally differentiated approach to RNAi Therapeutics drug development and it will be exciting to see where the Dowdy group and Solstice Biologics will take this versatile platform for RNAi and potentially beyond.

VC Investment in RNAi Therapeutics Platform Technology Symbolizes Turning Point

The news this week that a young Southern Californian start-up has raised $18M in VC funding may not seem that much of an event in the greater scheme of things.  Considering, however, that it concerns an RNAi Therapeutics platform technology, the investment by VenBio and Aeris in Solstice Biologics deserves our full attention.  In fact, it suggests that the RNAissance (Take 2) has finally worked its way through the biotech investment food chain.

Investment suggests Big Pharma appetite for RNAi Therapeutics

After Roche announced that I would leave the field a little more than two years ago, RNAi Therapeutics platform plays were shunned by the VC community as untouchable outcasts.  More so than the knock it gave on the confidence about the technology, the Roche exit, and following that related moves by other Big Pharmas, was interpreted as if Big Pharma demand for the RNAi Therapeutics platform was gone forever.   

As Big Pharma interest is critical to platform plays because it provides them with critical access to capital through technology licensing and perhaps even an exit, the perceived lack thereof dried out VC funding for RNAi Therapeutics.   

Looking at the people behind VenBio, one would have to think that they did their due diligence on this important matter such as by talking to Big Pharma about RNAi Theraspeutics directly. Corey Goodman for example is a well known, well-connected drug hunter and biotech entrepreneur who in 2007, as the President of Pfizer’s Biotherapeutics and Bioinnovation Center, talked about his and Pfizer’s interest in RNAi Therapeutics.   

And yes, the renewed confidence may not come all that surprising given the clinical results that the field has produced over the last year, but it's very encouraging to see it come from VCs.

Technology behind Solstice

Unsurprisingly, the investment at issue is aimed at developing RNAi delivery technology, currently the main driver of platform value.  The idea here is to add to the RNAi trigger chemistries that reversibly mask their negative charge so as to facilitate cell entry.  Once in the cytosol of cells, enzymes chew off the masking chemistries to reveal the RNAi trigger.

The idea is not entirely new.  In the antisense field, morpholinos take a similar approach to traversing the cell membranes in a neutral/slightly positive charge state.  In RNAi Therapeutics, Merck according to their partnering website is actively soliciting for such technology solutions.  If I may say so, the idea has even crossed my mind and probably means that everybody else had similar ideas even before that.

I would therefore have to believe that either the charm of or the particular solution by the inventor Steve Dowdy (who also happens to be the scientific founder of just-bankrupt Dicer dsRBD RNAi delivery company TaversaTherapeutics) has particular promise in the eyes of the investors.  I’ve only had time to skim through the patent applications, esp. WO 2010/141471, so I do not want to speculate too much about the prospect of the technology by Solstice (shameless advertisement: I can always be had for due diligence, of course).

Take the survey on the top right-hand side: Which Big Pharma company will make the first significant RNAi Therapeutics move in 2013? Merck, Novartis, Takeda, Pfizer, or Company X?