RNA Therapeutics and Oligonucleotides

Yet another breakthrough in the area of #GeneTherapy. Gene therapy restores vision in first-ever trial for rare, inherited blindness. Atsena Therapeutics After the treatment, one patient saw her first star. Another saw snowflakes for the first time. Other patients were newly able to navigate outside of the home or to read the labels on their child’s Halloween candy. #AtsenaTherapeutics #GeneTherapy #RNAtherapeutics #RNAdrugs #RNAmedicines #RNAmedicine https://lnkd.in/d-BQf5pm

A groundbreaking trial suggests CRISPR used inside the body can be safe and effective. Read this amazing article at https://lnkd.in/eDuMZVtD #crispr #geneediting #biotechnology #genetics #medicalresearch

The discovery that enabled the development of effective mRNA vaccines against COVID (and now other viruses) is the lipid nanoparticle LNP. Other technologies in the approved mRNA vaccines (way to make 5’ cap, modifications, UTRs) are all avoidable/replaceable and are having a minor impact compared to the major impact of the LNP. In the early days when we developed the mRNA vaccines (1993 till 2012), only liposomes (e.g. cationic) were available and those formulations always induced very little antibody responses (but all induced detectable T-cell responses). As shown for example in Figure 3 of our article https://lnkd.in/eJsWqAD4 : MessengerMax (cationic lipid) gives high expression of luciferase in vivo (A and B) but when it comes to induction of antibody response, only LNP works well (D). The LNP has turned synthetic non-replicating mRNA (can be 5’ cleancap or 5’ ARCA or 5’ enzymatic cap, unmodified or modified m1pU, with long or short UTRs, etc) into a vector that induces strong B-cell responses. As far as I know, there is no alternative so far to LNP for making mRNA vaccines that induce high antibody titres

An important study to address the acetonitrile problem for large scale #oligonucleotide synthesis

On August 31st Ribo presented the first clinical data from our completed Ph1 study of the world´s first and most advanced hemostasis-sparing antithrombotic Factor XI (FXI) targeting siRNA asset, RBD4059, based on our RIBO-GalSTAR™ technology. We thank the European Society of Cardiology #ESCCongress, session chairs, and all participants in the session for the opportunity and attention. We look forward to continuing the further clinical development of RBD4059 based on our Phase 1 results. “We are excited to have progressed world’s first and most advanced FXI siRNA program, now into Phase2, based on these encouraging data from phase 1. The molecule fulfills the target product profile we set up to achieve in terms of clinically meaningful and relevant potency and duration, which clearly differentiates from all established anti-thrombotic therapies as well as profiles of all other FXI inhibition programs in clinical development, including small molecules and antibodies. Also, Ribo is extremely encouraged to see the low inter-individual variability in treatment response, which further strengthens the first- and best-in-class potential of the program” says Professor Li-ming Gan, CEO Ribocure Pharmaceuticals AB and co-CEO Suzhou Ribo Life Science, Ltd. Results in short summarized below: •RBD4059 demonstrated dose-dependent, predictable PK, and pronounced (>90%) and durable FXI activity and protein reduction in in the dose range of 50 mg - 600 mg. •Primary endpoint for safety and tolerability has been met - RBD4059 demonstrated favorable safety profile with no identified adverse safety signals across the investigated dose-range. •This first-in-human study supports the further development of RBD4059 as an anticoagulant that can maintain a high level of PD effect with every 3- or 6-months dosing regimen, with potential for enhanced compliance and low bleeding risk in chronic anti-coagulant therapy. •A randomized, double-blind, placebo-controlled Phase IIa clinical trial to evaluate safety, pharmacokinetics, and pharmacodynamics of repeated subcutaneously administered RBD4059 in participants with stable coronary artery disease has been approved by EMA and the first patient was enrolled on the 28th of August 2024 in Ribocure Clinic based in Gothenburg, Sweden. #siRNA

Silence Therapeutics plc has two wholly owned siRNA therapies now in clinical trials and one partnered program with AstraZeneca. Silence's CEO, Craig Tooman, discusses the need for good science, making smart business decisions, and cultivating partnerships. Steffen Schubert, Steve Romano, Elaine Anderson, John Paul Gabriel, Jeske Smink, Pablo Lores Lareo, Marie Wikström Lindholm, Lucas Bethge, Jorgen Wittendorff

Pleased to be able to share the topline results from our latest Phase III study, the first to show the effects of an siRNA therapy as a monotherapy in lowering cholesterol levels in patients at low or moderate risk of atherosclerotic cardiovascular disease. Thanks to all the V-MONO patients, investigators, site staff and Novartis scientists for making this possible.

Novartis going for expanded label for their RNA drug... Leqvio shown to lower cholesterol in patients at risk of atherosclerotic heart disease. The antisense RNA targeting PCSK9 was originally approved for a genetic form of high cholesterol. By and large the first siRNA targeting a broad (not rare) patient population, its target of PCSK9 is well proven so not surprising it lowers cholesterol. The writing was always on the wall that Novartis would try to expand the label for this medicine. This is partly why Blackstone bought 50% of Alnylam's (original developer) royalties on the drug for... $2B!! siRNA and oligos are slowly going mainstream and continue their successful commercial roll. Big question now is pipeline prioritization, thinking about novel targets, and where can these therapies be competitive compared to legacy biologics and small molecules. We're seeing more and more work in pipeline prioritization generally. #pharma #genetherapy #clinicaltrial

Oligos staying hot... Despite biopharma's "mud and stick" season, oligos remain a hot area. The market seemed to forget about them in the height of the pandemic in favor of mRNA and are now re-remembering they are a proven modality that generates real value for patients and revenue for their developers. https://lnkd.in/gs5piJGC With that in mind, a new RNA company out of Versant from the former team at Chinook Therapeutics trying to drug the kidney. Outside of the liver, the lung and kidney (and T-cells generally) are the areas of most interest (partially driven by delivery vehicles that can get to those organs / cells). The company also has an investment off the bat and partnership with Novartis. This shows real focus in their development plan to get to the clinic. Always important but especially now given the market and capital constraints. We have not seen the last of mega biotechs going under I'll bet. So oligos roll on... but... delivery delivery delivery. #biotech #genetherapy #drugdiscovery

So happy about our study in NAR Nucleic Acids Research (Oxford University Press) that was published online today in advance articles: https://lnkd.in/dRHX5EDx There we show how fluorescent analogues of ATP are spontaneously taken up by cells and then incorporated into RNA via the cells' own enzymatic machinery. This metabolic fluorescence labeling happens in non-engineered cells - cool! - and opens new possibilities in, for example, live-cell imaging. So proud of my PhD student Pauline Pfeiffer - you rock! This is curiosity-driven research at its best! Thanks go to many persons involved (Jesper Nilsson, Audrey Gallud, Tom Baladi, Hoang-Ngoan Le, Mattias Bood, Anders Dahlén, Morten Grøtli, Elin Esbjörner, FoRmulaEx, AstraZeneca, Anders Holmén, Malin Lemurell, Margaret (Maggie) Holme) and Chalmers University of Technology! LanteRNA (our startup sponsored by among others Chalmers Ventures, Life Science Invest, Chalmers Innovation Office and Almi Invest) will be able to provide this technology in the future.