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ProQR - The Art of Editing RNA
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www.dddmag.com/article/2017/09/art-ed... The Art of Editing RNA Fri, 09/22/2017 - 10:07am by Joanne Van Zuidam - Editor - @dddmag The editing of messenger RNA, or micro RNA, is very different than the editing that takes place with CRISPR-Cas9. The former edits the message; the latter edits the DNA. This holds promise in modulating biological processes to treat disease—without altering the DNA blueprint. Drug Development & Discovery (DDD) spoke with Arthur A. Levin, Ph.D. Executive Vice-President at Avidity Biosciences and a pioneer in oligonucleotide therapeutics about the evolution of RNA therapeutics and a new editing platform from the Netherlands-based biotech company ProQR called Axiomer Technology which can make single nucleotide changes to RNA in a highly specific and targeted way. DDD: What are the advances in our understanding of RNA’s role in biology? Art Levin: The science of RNA has come a long way from the original central dogma of DNA-RNA- protein. We learned in biology class that the purpose of DNA was to be copied into messenger RNA and then messenger RNAs were translated into proteins. What we’ve learned in the intervening years was that this was a gross simplification. DNA still holds all of the blueprints for all of the information in a cell and in an organism, but it turns out that a large fraction of that DNA is transcribed and only a small fraction of the transcribed RNA actually encodes for protein. That discovery has opened up a whole new way of thinking about RNA as a therapeutic. Originally we thought if we can target the messenger RNA we can prevent disease-related proteins to be expressed. That was the basis for siRNA and antisense therapeutics. You’d make an siRNA or antisense drug that inhibited the messenger RNA from being translated into a protein. We now know that there are other regulatory aspects of RNA and we can more broadly affect biological processes by affecting those regulatory functions. That opens up a whole new realm: Can we modulate some of the RNA modulators to modulate downstream effects? That’s a lot of modulations in a single sentence but it basically tells us that the level of complexity of RNA is much greater than just being the recipe for a protein. If you can modulate the accelerator or the brake that’s on the particular expression of a disease-related gene or a family of genes related to disease you can have much broader effects. DDD: When was that discovery made? Art Levin: This has been happening over the past 20 years. We used to talk about junk DNA—that there was all this DNA that didn’t encode for proteins. It’s not junk DNA at all. In fact, that stuff—essentially the dark matter of the genome—turned out to be very important for regulatory processes and it’s those regulatory processes that we’re learning more and more about with new types of RNAs being discovered almost on a yearly basis. To list a few, there are messenger RNAs, transfer RNAs, ribosomal RNAs, micro RNA, circular RNAs and long non-coding RNAs. There is this whole burgeoning field of trying to understand what all these RNAs do and their roles in certain diseases. And that’s really how things have gotten really interesting the last few years. Micro RNAs have their own function—they control the expression of a number of different gene families that have may have evolved together to be regulated by this single micro RNA. A micro RNA may modulate the expression of a dozen or more proteins, each one of them related somehow to a biologic process. So the complexity has grown and in the process we now understand how we can use RNA-based therapeutics or RNA-targeting therapeutics to address a number of different diseases. DDD: How is the field evolving? Art Levin: You might transcribe a specific sequence of RNA but now we’re learning that there are enzymes that can make changes to that RNA even though it’s already what we thought was a finished product. This is very different than editing DNA that we hear so much about with CRISPR-CAS. That’s editing the genome. Here, with RNA editing, you’re editing the product of the genome so you don’t have these issues with respect to worrying about hereditable changes in the therapeutic agents that you’re giving. If you make a change in CRISPR-Cas9 you could very well have a series of changes which may be passed on to progeny. Whereas with an RNA editing system, it works more like a drug. You can edit the particular messenger RNA to have the properties that you want, maybe you’ll make a edit in an inappropriate stop codon produced by mutation so that the whole protein is expressed or maybe you’ll make some other change could be beneficial. Agents that make these kind of changes in RNA will be drugs, and their effects will be reversible as the drug is cleared from the body. This reversibility is in contrast to CRISPR Cas9 where changes to the genome (DNA) are permanent. There are a number of different mechanisms that are now being employed in clinical studies under the broad rubric of oligonucleotide therapeutics. The bottom line here is that we’ve learned so much about how RNA plays an essential role in the regulation of gene expression and have identified new ways to exploit that knowledge. When you combine that with recent knowledge which demonstrates that cells are talking to one another using RNAs as a signal so cells will release what are called exosomes (small, essentially nanoparticles that cells are releasing that contain clusters of micro RNAs or other RNAs) which, once out in circulation, actually affect the biology of neighboring cells. The whole field has evolved into a rather complex understanding—and I’m sure we’re just scratching the surface. One of my favorite examples to illustrate this is that there are viruses that literally express human RNAs. In this case, many express micro RNAs so that when you get infected with a virus the virus then begins to control its own environment by modulating RNA expression of the infected host cell or the surrounding host cells. So if nature is using RNAs to control a cellular environment, why can’t we? DDD: Is this the future RNA therapeutics? Art Levin: There are going to be all kinds of different ways you can modify the disease process but you can think of it broadly in terms of destruction of RNAs, editing of RNAs or replacement of RNA (either miRNAs or now mRNAs) . But in the end, independent of mechanism it all comes down to the key problem in oligonucleotide therapeutics: delivery. The field is now coalescing between two basic areas: one is can you deliver the drug in some sort of targeted, specific manner, and a number of companies are doing that. The other way to deliver is locally. ProQR has chosen for the most part to deliver the oligonucleotide to a disease-specific site. So for instance, in their cystic fibrosis program, QR-010, the drug is inhaled and delivered directly to the lung. For ProQR’s ocular programs the drug is delivered directly into the eye and finally for their dystrophic epidermolysis bullosa (DEB) program, they are delivered directly to the skin in a topical application. ....zie vervolg
...vervolg The most successful oligonucleotide therapeutic, which is Biogen’s Spinraza, is delivered locally into the central nervous system via intrathecal injection for spinal muscular atrophy. Sarepta Therapeutics recently had a drug approved for muscular dystrophy. That drug is a splice switching oligonucleotide. What happens in muscular dystrophy is that there might be a miss-sense mutation in one of the many exons in the dystrophin gene and if you design an oligonucleotide that binds to the right place on the messenger RNA you can actually get the translation/editing machinery to skip the bad exon and then continue the translation of the protein to the next good exon. That allows you to make maybe a shorter version of the protein but it will still work. One of the criticisms of that drug is you don’t get very much of the drug to the muscle. At Avidity Biosciences, we have developed a powerful technology called antibody-oligonucleotide conjugates, for delivery of oligonucleotides to multiple cells types and tissues. In the case of muscle, for example, we use an antibody that binds to muscle cells and allows for the internalization of that splice-switching oligonucleotide. With these targeting technologies comes the promise of much more effective delivery. DDD: What are the advantages of oligonucleotides? Art Levin: Oligonucleotide therapeutics still represents the best and most direct application of the information from the genomics revolution for the design of medicines. You simply need to know the sequence of the disease-related RNA you want to target to address you can design an oligonucleotide using Watson-Crick base-pairing rules to modulate its function. You don’t have to spend ten years doing small molecule structure activity relationship trying to find the small molecule that binds to an enzymatic pocket. Which is how most of the drugs we take on a daily basis work. You would simply know the RNA sequence for the specific disease-related RNA and then you can make a complementary sequence which will recognize that and either edit it or get it to skip or inhibit its expression. The other reason I’m bullish on oligonucleotide therapeutics is that we now know nature uses RNA to modulate gene expression. The example I gave you of the virus that encodes specific human micro RNAs to modulate their environment? They express certain RNAs when they’re latent, and express others when they want to be active. We know RNA is a tool for intracellular warfare, for genetic warfare and that tells me that RNA is clearly an important way to modulate biological processes. DDD: How does Axiomer technology fit into the future? Art Levin: In a world of the original central dogma of DNA-RNA-proteins, we never thought that the RNA somehow could be changed once it’s been transcribed. And in fact, what the Axiomer technology is utilizing is an understanding that there are enzymes available in our cells which are set up to do particular modifications to that existing transcribed messenger RNA. The particular change that they make is they can change particular adenosine (A) to an Inosine (I) which is read as a Guanosine (G). So instead of that A pairing up with a T, that A gets transformed into a G equivalent that will bind to a C or that will encode for a different amino acid in a protein. What the scientists at ProQR have done is figured out a way to develop synthetic oligonucleotides that will go in to a cell and attract these particular enzymes through a particular site on the mutated RNA or on the RNA that they want to change the expression pattern of and they can make the change in a very focused and directed way. If you have an inappropriate UAG in a messenger RNA that encodes for a stop, that’s where the translation machinery will stop and you won’t do anything past that signal. But what if that A happens to be a mutation? And all of a sudden you’re stopping the formation of a particular protein because you’ve found a mutated site than now encodes for a stop sign and doesn’t allow the rest of the gene to be described. Imagine if you can make a change to that A and make that UAG stop sign into something else. You can get the protein to be synthesized in the appropriate way. That is the nature of the kinds of things you can do with the Axiomer technology. The siRNA world and antisense world are trying to chop up the messenger RNA or tear up the Xerox copy of the DNA that is messenger RNA and stop it from being translated. The Axiomer technology actually allows for the translation but it changes the recipe for that protein slightly. What the Axiomer technology allows you to do is if you know the sequence of a particular gene and where you want it to be edited you can produce the specific edit at the exact spot that you want it at. That is a completely novel technology as far as I know. DDD: What can you tell me about ProQR’s drug development? Art Levin: The focus of ProQR is using RNA therapeutics in rare genetic disorders. We talked about one mechanism, exon skipping, where you might have a mutated exon that you don’t want to be encoded anymore. It might ruin the protein that’s about to be translated and you can skip that. So there are a couple of different drugs that ProQR is working on that work through that mechanism. Their Leber’s Congenital Amaurosis (LCA) drug works through that mechanism. LCA is an inherited disease that causes blindness. Their drug for Dystrophic Epidermolysis Bullosa (DEB) also works by skipping.
vervolg DEB is a terrible disease. It’s a disease of collagen 7 which is in the skin and if you don’t make collagen 7 essentially your skin is easily peeled off. So a baby being born and going through the birth canal might have parts of their skin pulled off by the friction or in life any friction can cause blistering or skin loss. These people spend their whole lives trying not to produce any stress or strain on their epidermis—it’s like potentially having burns on your entire body. What the team is trying to do here is make a functional copy of collagen 7A1, from a non-functional copy that these people have inherited. In the disease state it has a mutation in it that doesn’t allow it to perform the anchoring function that collagen 7A1 takes on in healthy people. So by skipping a bad exon you can create a functional collagen 7A1. It may be a little shorter, it might not have the number of turns that a collagen 7A1 helix would have, but it has most of them. The hope there is that you can create a situation that a patient’s skin will gain some of the tensile strength that your skin and my skin have so that every time these patients rub their hands they’re not going to have the blistering or loosening of that top layer of skin from the dermis. DDD: Where are these drugs in the regulatory pipeline? Art Levin: LCA has an IND that has been accepted and ProQR is getting ready to enroll their first patients. It’s a very exciting time for the company. The cystic fibrosis program is well into clinical trials and due to report out shortly. It’s a very exciting drug and I think the industry at large is waiting for that to come out. [Editor’s note: ProQR received orphan drug designation from the FDA for their drug candidate QR-313 for Dystrophic Epidermolysis Bullosa following our interview with Dr. Levin.] DDD: What are the challenges of RNA therapeutics? Art Levin: Some of these disease have multiple mutations and each of those mutations would require a unique RNA therapeutic. This is something that differs from other therapeutic areas. For instance, in muscular dystrophy there are at least 17 different exons that need to be skipped so each of those patient classes would require a different drug. Same thing with LCA, Ushers, and DEB. Each of those diseases have patients that may ultimately require a different sequence—same philosophy or same mechanism of action—but you want to make the change at a different place on the RNA for each of the different patient classes with respect for which mutation they may hold. That said, there will be variations in individuals. Take muscular dystrophy for example, most parents know what their son’s genotype is, so you know which drug, or which exon you want skipped. For some of these debilitating, genetic disorders, sequencing is now the norm. Right now, would it be important to know what your DEB mutation was? Maybe not, but as we get closer to getting different formulations for different patient subtypes then you’ll see that the patients will get the sequencing done and you’ll know which specific sequence drug you’ll have to take. Moving forward the oligonucleotide field and companies like ProQR will develop novel ways to utilize RNA targets for modifying disease processes as we learn more about RNA biology and you should expect to see advancements in how we deliver these important new drugs to the right cell types to make the process safer and more efficacious. Arthur A. Levin, Ph.D. Scientific Advisory Board Member, ProQR Therapeutics, Leiden, the Netherlands Arthur A. Levin, Ph.D. has been a scientific advisor for ProQR since its founding. Dr. Levin has nearly 20 years of experience in the research and development of RNA-targeting therapeutics and 30 years of experience in the pharmaceutical industry. He has been involved in the development of more than 20 oligonucleotide therapeutics in clinical trials. In addition to the Scientific Advisory Board for ProQR, Art is Avidity Bioscience’s Executive Vice President of Research and Development and sits on the SABs of Rigontec, CiVi Therapeutics and Cardior, and is a Director at Stoke Therapeutics. Prior to joining Avidity, Dr. Levin ran Research and Development at miRagen Therapeutics and was Chief Development Officer at Santaris Pharma (Copenhagen) where he led the efforts on the first microRNA targeting therapeutic in clinical trials. Before joining Santaris Pharma, Dr. Levin consulted for leading biotechnology and pharmaceutical companies, conducting research and development in RNA-based therapies such as mRNA, microRNA, and siRNA. Dr. Levin’s began his work in oligonucleotide therapeutics at Isis Pharmaceuticals, where he was Sr. Vice President of Drug Development and responsible for the development of Isis’ products across a range of therapeutic areas. His expertise was instrumental in advancing more than a dozen oligonucleotide drugs from basic research to clinical development in areas such as neuromuscular diseases, infectious diseases, metabolic disorders, cardiovascular disease and cancer. He joined Isis from Hoffmann-La Roche Inc. where he was Research Leader and made fundamental discoveries in retinoid therapeutics. Dr. Levin holds a Ph.D. in Toxicology from the University of Rochester School of Medicine and Dentistry, New York and a B.S. in Biology from Muhlenberg College. He completed his post-doctoral work at the Chemical Industry Institute of Toxicology in Research Triangle, North Carolina. He the author of more than 70 papers and book chapters.
grenzeloze potentie dus!!!
Hoe ver zou het staan met de klinische validatie van het Axiomer platform? Het wordt tijd voor een bevestiging. De kunst is inderdaad de "delivery"in de cel. Zouden ze gebruik maken van de club van dhr. Levin? Zou wel gaaf zijn: "At Avidity Biosciences, we have developed a powerful technology called antibody-oligonucleotide conjugates, for delivery of oligonucleotides to multiple cells types and tissues. In the case of muscle, for example, we use an antibody that binds to muscle cells and allows for the internalization of that splice-switching oligonucleotide. With these targeting technologies comes the promise of much more effective delivery". Hebben ze gelijk de Katwijkse ziekte een slag toegebracht zou ik denken.
Bij gebrek aan witte rook rond DEB herhaal ik hier nog maar eens een stuk van De Boer over Axiomer dat recentelijk gepubliceerd werd:drug-dev.com/rna-editing-new-editing-...
Veel geintresseerde lezers op SA snappen niet zo veel van van de Axiomer technologie: het wordt tijd dat dit meer in de publiciteit komt. Ook de reden van het half mislukken van de DEB trial werpt een smet op het wel of niet werken van deze technologie: NDHT "Good to read. Wish more discussion on their Axiomer technology. They claim that there are more than 20,000 G - A mutations causing lots of diseases. The Axiomer can do an A - I editing. Because I is translated as a G, this would solve the G - A problems. I have tried to read several times and still could not comprehend their "unique" technology. They do not have any meaningful partnerships. Maybe none of their potential partners understand this G - A or A - I things, neither? :-) 14 Mar 2019, 12:35 PM" Culleraa: "Me neither... but the idea is to use the cell's own enzyme to do editing of the RNA... to modulate the protein expressed. 100% human biology vs eg crispr. And not limited to single gene GA issues... could modulate really any protein. If Axiomer can really be used as a therapy would make the Moderna platform look small! But so far only Galapagos is using it... so not priced into the stock, i'd say..!"
Na het in maart verschenen stuk over Axiomer is het wat stil geworden. Wordt tijd voor hernieuwde belangstelling voor deze vinding nu Crispr/Cas9 steeds meer wordt weggezet als zijnde te onnauwkeurig.
Leesvoer voor de komende regenachtige dagen tav ASO en RNAi techniek, hier wordt het in mijn ogen redelijk duidelijk uitgelegd:www.ncbi.nlm.nih.gov/pmc/articles/PMC...
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