Twenty years ago, using worms, two American biologists demonstrated that they could efficiently and selectively dial down the expression of various genes by injecting small quantities of siRNA. By 2006, the biologists, Andrew Fire and Craig Mello, had received the Nobel Prize in Physiology or Medicine and pharma was already pouring billions of dollars into RNAi drug development. (1)
Fast forward just a few years and pharma was already exiting the space, not because of the lack of potential of, or the mechanism behind RNAi, but because of its delivery challenges.
Short-interfering RNA (siRNA)-induced RNAi responses have great potential to treat a wide variety of human diseases from cancer to pandemic viral outbreaks to Parkinson’s Disease. Moreover, siRNAs have the potential to pharmaco-evolve their targeting sequence to keep pace with mutations in diseases driven by genetic change, such as cancer and influenza, a property that no other clinical modality can perform. However, before siRNAs can become drugs, they must overcome a billion years of evolutionary defenses designed to keep invading RNAs on the outside cells from getting to the inside of cells. Consequently, since the beginning of the RNAi therapeutic revolution, the problem to solve has remained the same: Delivery! Delivery! Delivery! Indeed, all other issues with developing siRNAs as a therapeutic modality have paled in comparison to the delivery problem. (Springer & Dowdy, 2018 p.109) (2)
Delivery systems for siRNA must overcome three major obstacles: getting the drug to its target in the body, getting it inside the cell, and releasing it.
Once it is systematically administered into circulation, siRNA is swiftly degraded into fragments, thus preventing the accumulation of intact therapeutic siRNA in the target tissue. It was discovered that encapsulating siRNA within lipid nanoparticles could be an effective way of protecting the entrapped siRNA from nuclease attack and renal clearance and transporting siRNA to targeted tissues and cells. But even as scientists got better at solving the challenge of getting particles containing siRNA into target cells, escaping the endosome within the cell remained a problem.
Describing the importance of this last step in the drug delivery process, Akin Akinc, Associate Director of Research at Alnylam said “If the particle is unable to escape the endosome, it enters into a degradation pathway. Basically, it’s game over.” (Akinc, 2009) (3)
Alnylam persevered with its siRNA development and went on to achieve success, receiving the first approval for an RNAi therapy in both the US and EU in 2018. Although that therapy, Patisiran, is delivered by lipid nanoparticles, Alnylam and other companies have since shifted focus to GalNAc conjugation for RNAi delivery into the liver. GalNAc not only binds strongly to a receptor that is expressed abundantly in the liver, it also has less toxicological burden, is easier to make, lasts longer and is easier to administer than lipid nanoparticles. (1,4)
Consequently, the overwhelming majority of siRNA therapies currently in development target the liver.
Herein lies both the remaining challenge for siRNA therapeutics and the opportunity for PYC. When I asked Rohan Hockings today about the potential benefits of CPP-LNP delivery of siRNA compared with GalNAc-mediated delivery he responded
GalNAc conjugation is only applicable in the liver and targeting hepatocytes specifically within that organ. The CPP-LNP combination, in contrast, has the potential to be used across a very wide range of target cells and tissues.
In March last year, it was announced that PYC was collaborating with Prof. Dan Peer at Tel Aviv University, with the aim of evaluating the complementarity of utilising CPPs and LNPs in the delivery of siRNA to tissues outside of the liver. Dr. Katrin Hoffmann, Phylogica’s Director of Research commented:
RNAi therapeutics have great potential but delivery beyond the liver remains a key challenge. We are excited to work together with Dan Peer, a leading expert in the systemic delivery of siRNA using targeted nanocarriers. This collaboration will provide important proof of concept data towards the delivery of siRNA/LNPs using our CPPs to develop more potent and safe RNAi therapeutics. (5)
Results of that collaborative work with Dan Peer were announced this week. It was demonstrated in in vitro models that PYC’s Cell Penetrating Peptides (CPPs) embedded in the surface of Lipid NanoParticles (LNPs) achieved a substantial improvement in efficacy of the LNPs with no observed toxicity. It was highlighted in the announcement that improved transfection efficiency (efficacy) is the key to broader uptake of LNPs as a delivery technology for gene therapy. (10)
But the question remains – having exited the space, does pharma still hold interest in siRNA therapies?
The answer would seem to be yes.
The approval of Alnylam’s Patisiran in 2018 marked the beginning of a pharma drift back to RNAi therapeutics, evidenced by substantial deals by the likes of Regeneron, Eli Lilly and J&J. (6, 7, 8, 9)
PYC has also seen increasing interest, stating in the siRNA collaboration announcement last March
Delivery of siRNA inside cells is an area of substantial commercial interest to Phylogica’s prospective pharmaceutical and biotechnology partners. (5)
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