Monday, November 17, 2014

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.


Anonymous said...

Seeking the Right to Try
Laws allowing terminal patients to try drugs not approved by the FDA have passed in five states, but experts question their efficacy.

Christine McSherry's son Jett is a typical college freshman trying to push for as much independence as he can. But Duchenne muscular dystrophy, a disease that tears away muscles, has taken his ability to walk. He relies daily on aides to help him with homework, eating and carrying classroom materials.

"He feels he has regressed to being a young child," McSherry says. "It's a horrible paradigm to be in."

Jett is planning on majoring in history and is enjoying the social aspects of his college outside of Boston. Soon, he'll begin a clinical trial that he's been waiting two years to participate in, and his family hopes the experimental drug – eteplirsen, made by Sarepta Therapeutics – will stabilize his condition and give him a longer life.

[READ: The New Normal: Adjusting to Life With Lupus]

There is no cure for Jett's condition, which is fatal, but parents like McSherry believe there is hope if they can bypass government bureaucracy and gain access to medications still being tested by scientists. "If there was a drug to treat my son's disease, then he would at least have the right to try it without long and expensive waits for it," she says.

Some states are making this process easier, passing laws that allow terminally ill patients access to drugs that have not been approved by the government. In Arizona, such a provision quietly won approval during the midterm elections.
A map depicting which states have "right to try" statutes.
Click for a larger image.
This type of measure – passed also in Colorado, Louisiana, Michigan and Missouri – is known as a "right to try" statute.

Anonymous said...

Revisiting a question from a year ago. Are you still interested in starting your own fund or would you want to join an existing healthcare fund? Or would you prefer to stay with research and do the investing on the side? Have the markets proved rational enough to reward your data-driven predictions or else can you reliably enough anticipate the market's somewhat irrational reactions to science-based companies?

Dirk Haussecker said...

I am quite happy where I sit right now, but would always entertain ways to grow my technology and financial market skills.

Anonymous said...

Interesting, doesn't Solstice use your much maligned ddRNAi tech?

Anonymous said...

Are you sure Dirk has maligned ddRNAi, or was it rather the lack of a company championing its cause that he's bemoaned?

Steve Dowdy said...

Neither Solstice nor my academic lab are using ddRNAi. We are strictly using siRNNs with various phosphotriester groups on them.

Anonymous said...

None of it means anything until it is validated by a third party.

Where is PFE?

Anonymous said...

There is a share chat site in Australia called Hotcopper. The protagonists of BLT there are usually hamming BLT up with all the enthusiasm of pubescent schoolboys.

Recently, they have gone as quiet as a mouse.

If this does not forbode the end of BLT then nothing does.

Anonymous said...

Too right about the end is nigh for BLT.

Close inspection of the trading over last several months indicates the higher volumes and prices is the ruse to flush out the long term holders and stale bulls so as to increase the ownership percentage without scaring the horses to a high price.

Takeover by stealth.

Must be why Voyager isn't worried about patent issues.

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