Let’s Go to San Francisco: Trends from the 4th RNAi Research and Therapeutics Conference

Still looking for an interesting RNAi Therapeutics conference to attend? The 4^th RNAi Research&Therapeutics conference to be held in San Francisco June 20-21 may be a good choice to satisfy your cravings for not only RNAi Therapeutics research and development, but also the wider applications of RNAi gene silencing for target identification and new interesting trends in targeting non-coding RNAs.

Register with discount code ‘RNABLG13’ for 20% discount and free RNAi Therapeutics blog T-shirt here.

Reading through the abstracts of conferences like this one is helpful in understanding the trends in a scientific field.  As an appetizer, the following will highlight a few of those promising scientific directions, challenges, and future investment flows as seen through the lens of an RNAi Therapeutics nerd.

Delivery, delivery, delivery

An old headline, but as the key value-driving effort, delivery naturally is a focus of an RNAi Therapeutics conference.  Importantly, the two most advanced and promising systemic delivery technologies, SNALP/LNPs and DPCs, are represented.  Pieter Cullis, an academician with ties to the Tekmira, AlCana, and Alnylam love triangle, will be talking about Tekmira-type LNPs.  Interestingly, while these LNPs are known to have applications for knocking down genes in the liver, solid tumors, and potentially sites of inflammation and lung epithelia in aerosolized form, the abstract notes their use in the central nervous system (CNS) for serious neurological disorders.  Of course, the CNS is the organ with many of the major unaddressed medical needs, so I am curious whether there will be actual data showing good distribution and efficacy of LNPs in this organ.  While I consider the CNS challenging in terms of achieving wide distribution with direct administered nanoparticle-based delivery technologies, the immune challenges of nanoparticles, including complement activation and phagocytic uptake, might be lessened in this organ.

David Lewis from Arrowhead Research will present the latest about the exciting DPC delivery technology, including data from the chronic HBV program (ARC520).  By then, IND-enabling tox studies for ARC520 should be completed and the first DPC-related IND filed.  His talk should also be of interest to those not as obsessed about DPCs as I am as he will speak about some of the mechanistic insights of the key endosomal escape process, insights which should be more broadly applicable.

Trinna Cuellar from Genentech will be speaking about ‘A systematic evaluation of antibody-mediated siRNA delivery and silencing’.  It seems that Genentech hopes to create RNAi Therapeutics value based on its expertise in monoclonal antibody pharmacology.  The talk should elucidate whether the strategy envisions only minimal antibody-siRNA conjugates, or whether it further embraces other delivery platforms.  Of note, Tekmira once mentioned that it had a technology evaluation with Genentech on antibody-targeted SNALPs and made the bold prediction that ‘Roche will be back’.

Curiously, not one but three presentations concern aptamer-targeted RNAi trigger delivery (note: aptamers are antibody-like nucleic acids).  We have had a number of reports of such aptamer-siRNAs, especially for cancer and HIV infection.  However, these reports have encountered much disbelief, especially since they lacked an explanation for their postulated endosomal escape.  With credible knockdown activity reported with the GalNAc-siRNA conjugates by Alnylam, aptamer-RNAi triggers should be similarly gaining in credibility, especially when combined with self-delivering RNAi trigger chemistries.  An experiment that I would like to see as part of the field regaining credibility is an ASGPR-targeted aptamer-RNAi trigger conjugate (ASGPR is the receptor targeted by the GalNAc sugar).  In addition to building confidence in the approach, it would also be an alternative to GalNAc-RNAi triggers should the sugar moiety cause injection site reactions in humans.

Some of the aptamer-RNAi trigger presentations also touch on the subject of bifunctional RNAi Therapeutics, meaning RNAi Therapeutics formulations with a second non-RNAi therapeutic activity.  These secondary activities may include receptor blocking or toll-like receptor (TLR) activation as in a talk on CpG-STAT3 siRNAs by Hua Yu from the City of Hope.

In ddRNAi it is about the RNAi trigger design

The conference also includes presentations on microRNA processing and their implications for ddRNAi trigger design.  Unlike in RNAi Therapeutics induced by synthetic RNAi triggers, RNAi trigger design remains a crucial value-creating activity in DNA-directed RNAi Therapeutics.  Unfortunately, its importance has been entirely lost from the commercial field (if you really want to aggravate me, show me a U6-driven shRNA being put into clinical development).  Fortunately, academic efforts mean that ddRNAi trigger design continues to advance.

In his Keynote address, Mark Kay from Stanford University will present insights from his lab on microRNA processing and, crucially, how that knowledge can be put into practice for ddRNAi Therapeutics.  Especially recent work from Shuo Gu in his lab on Argonaute-specificity, strand selection, and Dicer processing have advanced this field and should also provide for fresh ddRNAi IP opportunities.  A presentation by Marco Weinberg from the Scripps Research Institute meanwhile is focused on an earlier step in microRNA processing, the primary microRNA recognition and cleavage by the Drosha enzyme.  ddRNAi trigger cassettes requiring the Drosha processing step promise to be more natural and cell-specific alternatives.  

MicroRNAs hot, lncRNAs getting hot

Functionally closely related to RNAi, it is not surprising that the conference program includes microRNA Therapeutics.  As by far the most advanced microRNA Therapeutics program, the update on the anti-miR122 program by Santaris for HCV infection (phase II) will be a highlight for those that have not been paying close attention to the results.  For those more familiar with the story, it will be of interest how Santaris aims to position this innovative treatment approach in an increasingly crowded and competitive field.

There will also be presentations on long non-coding RNAs (lncRNAs) and their therapeutic use.  LncRNAs are RNAs that do not code for proteins and are usually expressed in between protein-coding genes or antisense to or just upstream of protein-coding genes.  As more and more examples of such functional non-coding RNAs emerge, a whole cottage industry has emerged to cater to them.  Interestingly, reports suggest that lncRNAs can often be suppressed by RNAi triggers.  This is a departure from the classical thought that RNAi triggers can only target protein-coding mRNAs.  Similar to microRNA antagonists, targeting lncRNAs that silence other genes, can activate gene expression.  Oligonucleotide research reagent companies have naturally recognized the commercial potential of this by offering large lncRNA-targeting RNAi trigger libraries and Zaklina Strezoska will present the design approach by Thermo Fisher.

RNAi trigger libraries are also the focus of presentations by Michael McManus from UCSF and Iain Fraser from the NIH.  These researchers employ the libraries for understanding biological processes, an effort that is also suitable for new drug target identification.  The library approach by McManus is unique in that every gene is targeted by many (~25) shRNAs.  This is done to increase the confidence that hits concern real targets and not just some off-target noise.  The approach is critically facilitated by next-generation sequencing (NGS).

Next-generation sequencing is also the focus of a late afternoon session at the conference.  Since NGS is ubiquitous in today’s research, keeping up-to-date on technological advances in this field is part of the homework of any RNAi Therapeutics buff.

The conference will finish on a Friday.  If you like to digest all the information and be inspired by nature at the same time, I recommend that you stay the weekend and rent a car to see some redwoods, coastline, and villages inhabited by eccentrics north of the Golden Gate Bridge.  Good weather guaranteed.

Register with discount code ‘RNABLG13’ for 20% discount and free RNAi Therapeutics blog T-shirt here