 Okay, I will switch to English and I'm going to tell you a little bit of a more focused experience and, you know, try to try to tell you many, you know, many facts that happened when we start our company, my company and the lessons out of this so and essentially what we are going to What I'm going to talk today is about a discovery of a non-coding RNA that help us to start a biotech that essentially help us to address diseases by upregulation of endogenous proteins. So, one of the very important points that will come out in the in the discussion is that it is essential to do basic science fundamental science for innovation. And we were involved in exploring the transcriptome. So essentially we were looking at the genome and what the genome is encoding. And in this exercise where we were trying to make a catalog of all the protein coding genes. Accidentally, we identify a group of non-protein coding RNAs or non-coding RNA or non-coding RNAs. And this includes also antisense RNAs. So essentially RNA that are transcribed from the opposite strand and they will form some hybrid with sense RNAs. Another key word that is a serendipity also because those basic science project very often give you some discovery. And those discoveries, which you didn't plan at all are coming out from the, you know, from the basic science and it's up to you to identify new possible application and that your experiments are trying to tell you. And it is very important also that to think that the basic science is needed for innovation and a good having a very open eyes to the discovery is extremely important to have the idea to apply them for the discovery. Our project was mentioned to discover what the genome is transcribed and we have been over the years, this is a very long term project that we can to identify the protein coding genes and in this exercise we found that more than half of the genes are non-coding. Little by little, after a lot of skepticism, address and our group found that they are involved in the regulation of various activity of the genome. And particularly, I will talk about the regulation at this level, regulation at a translational level. And actually, out of the non-coding RNAs we estimate there are about 30,000, there is still something like 95% of them for which we don't know the function. We don't know that if all of them will be functional, but if you focus on the functional of those non-coding RNA and you identify new functions, it's likely that you may identify additional more discoveries that are different than what we have been. I'm going to talk now, but there are many chances to explore the non-coding path of the genome. The discovery came out in collaboration, so we have been organizing a phantom consortium where the RIKEN has been producing, RIKEN is one of the main Japanese research organizations, has been producing a very large database of full length CDNAs, so essentially a copy of transcribed genes. And in this analysis, my collaborator, Professor Stefano Gustińczis at IIT, the time he was at CSAN in Trieste, was interested in the UCHL1 because UCHL1 is a gene involved in Parkinson's and we identified this antisense represented here in red, before splicing, after splicing, essentially this overlaps this region of the UCHL1. And because the antisense was potentially interested, they started to over-expressed and to see if there is any regulation. But RNA level was very disappointing, so there is no regulation of RNA level. And just before throwing away the whole project, a Claudia Carieri, the first author, decided to see what happens to the protein in western blot. And actually in the presence of the antisense, the sense produces much more protein, so it's between five-fold to ten-fold in that experiment. We have one antisense that does not cause changes at RNA level, but it causes a dramatic increase of proteins. We start to look at what is important, and we identify in this region here, it's not shown here for, not to expand my presentation too much, but there is a sign element here. And after many experiments, in particular changing this antisense region to artificial, putting artificial antisense against any target RNA, and trying the effect of the sign element, which is represented here, we identify a new class of antisense RNA that we call sign-ups, because there are antisense that have a sign element that upregulate the protein translation for the RNA that they target through this binding domain, which is essentially a complementary sequence, and it can be synthesized with a lot of flexibility, and actually it works for the majority of RNA that we have been testing so far at some different level. So essentially, you're all familiar with SI RNA and inhibition of protein translation or gene activity, this is enhancing, those are antisense-enhancing protein activity, and that can be customized and work on endogenous RNA. So what we decided to do is, of course, we started many validation. This is one collaboration with the Telethon Institute in in in in in net poles, and actually we wanted to see if the sign-up design against this gene, sign-up against the COX-7B, which is a gene involved in microtermia with a linear skin lesion, when there is only one copy of this gene. So here's the human phenotype, and this is the Medaka fish COX-7B. The model consists in inhibiting splicing, so reducing to about 30% the fully spliced COX-7B, so 70% does not contain the X2, which is important for the function. And then to try to rescue to this phenotype by adding one antisense, essentially antisense with our sign element connected to see if it works to rescue the phenotype. And actually it works in about 50% of the cases, the size of the head that the development goes back to normal if compared to our control, and those are all the data, all the details, everything is in the paper. So essentially we have demonstrated that that could work to rescue a phenotype. We have been thinking a lot, and the idea is that to use sign-ups as a tool and therapeutics tool, but also tool for various other applications. There are at least 300 healthy sufficiency, so what are healthy sufficiency, healthy sufficiency are diseases where one copy of the gene is mutated, and so it's not functional. And the decreased dosage, you see the number of protein is normal protein, so half the amount of the protein is sufficient to cause a disease. And the idea is to use the sign-up to rescue the translated to use the functional copy of the only gene that is working, but to make it more protein, and to rescue the level of protein so essentially to have a therapeutics sign-up. And we had various ideas about the application, so using the sign-up against any other RNA, so of course to increase the translation of protein without changing the level of RNA. So this could be used for biotechnology in the lab, for bioproduction, to produce, for instance, more antibody for therapeutics, of course, as a whole sufficient is one of them where we're going to expand later about the possible application. And the first part, I mean, one very important part is to think very well about intellectual property. And intellectual property is fundamental, and as a scientist you need to understand the importance of intellectual property, what is the meaning, and how you will use it to be able to use and to be able to protect the areas where your biotech is involved. So you cannot get funding if you don't have a protection for a given area. And in our case, we were very happy to find that there was no such finding, and so basically the likelihood to get intellectual property was very high. And in fact, we filed the first pattern that was in collaboration with Enrique and the CISA, that was the host institute of Stefan Augustincic. This was granted a few years later in the USA is a very broad umbrella pattern that covers antisense RNA, and with the non-overlapping part containing a sign element that has the function to to enhance protein translation, sign element and also sequence similar to sign element. So it is actually very broad and fundamental. But also what we continue to do, we continue to look at ways to protect, to further protect, and we have additional filing about structures and other ways. So it's very important this strategy to really have strategies, a serious strategy to create multiple barriers to further protect your area of interest. This interest for the pattern came was not only at this time, but I know I was involved in filing patterns many years earlier when we were developing genomics and methodologies to capture genes. So I was fairly exposed and also with some experience in consulting for some of the spin-off of the Rican Institute. And so we were ready to go and we learned how to start a company. And the first we really want to be sure about the technology we tested in different lab. We have a plan and business and the business plan, but as always, you know, you make a plan is important to make a plan and very often you go in a different direction. So what we wanted to do, we wanted to develop a platform to make a synapse as a strong technology for broad application, we were thinking about antibody production at first, and without thinking that the therapy is maybe too complicated, and then we change our mind in the middle and you will see where. Actually, it's very important part that you need to plan beyond what is just a paper or a patent. The patent is just enabling, but you need to prove and have a lot of experiment of proving that is useful. So we started to do this. We have various experiment and then we went to for the company and we created the TransSign Technologies as a what was called Rican Venture. Rican was the institute in Japan and it has this system to create a venture so could provide support. The support that Rican was very good. Actually, here is the details of the company. I started from myself and Stefano and here are a few more things about us. Essentially, we want to say we are basic scientists that very, very much interested in publishing our research, that move suddenly moved, split our attention also to start some company. And, you know, you have your plan and then it worked very well until we started the company but then we wanted to get to get funding and the company was based in Japan. So we were required to provide more proof of concept. The idea is not only to work in with the medaka fish but also work with the mammalian, go with the mouse with the idea that we will raise some. And here many problems start to happen because we were often told by a fairly conservative investing environment that is too early and we must provide plenty of evidence before they would like to invest. So we were left with the lab there and making many experiments in the lab but also with this struggle to really, you know, really think how to make that kind of evidence before we could get. And time was moving anyway so we needed to accelerate to do something. So, and here I would like to really break, you know, to really comment why it was so difficult to get any funding because we were based in Japan where the attitude is fairly risk adverse. So it is not possible without evidence and there are many people involved without experience as venture capital. There is a very little support and no risk of takers and if you failed you have no future chances. And if you go to the big pharma, there is not enough time to really develop the technology before the big pharma usually stops because they need return of investment in much shorter time. And if you go to US they say it is interesting so let's invest to produce the evidence and and even if you fail, that's fine because investing in many spin-offs. Some of them would be excellent and be a Moderna or that size and even if other five company will fail and one become Moderna, there's still a huge return. And the failure is just one way to really understand what works and what does not work. And so essentially we've been looking at this and actually this was not only by me but Kubota-san at the Peppi Dream that is a very successful biotech company in Japan at this meeting was fairly inspiring. And anyway we decided to know we've been thinking a lot what do we have to change to really get the company successful so we have to produce the POC and we were working to make the POC as a virtual company, so essentially working in the lab under proper agreement with our institution and through collaboration with other academic institutions. So really working like in a garage for a while to produce to to get evidence and getting the documents. We're also making some cash because there was some request to synthesize the synapses so the company was selling artificial we could design them we were selling some of those. We could survive and paying for the patent fee and all the other costs without without having funding. It is fairly unusual because usually you have some funding we didn't have any except sometimes going to our own bank and help ourselves with that. The environment has been fairly hostile so we had the review for the reconvent your system and this virtual model was not recognized so we were told so I told them we are developing new IP and going to the POC. The reviewer said oh you don't have the employees this is not a company so please quit the quit this system so it was a rejection. We are not doing well and it's losing the reconvention status we could not use any more our labs we all the collaboration agreement failed so but the company had already accumulated quite a quite a big amount amount of data with proper agreement and everything was was clear and and as a company. Founder the mission is to keep the company alive and the ideas alive. Now the important point is that they were not only Stefan and Piero here, but there were other members. We've been working as a team and so Hatsuki have been developing many aspects of the technology this is RNA biologist that we can Michael Johnson he's a. field was generated but then he's been in business and Sylvia and Claudia was involved, unfortunately Sylvia passed away. Three years ago in this day she has been really really very important for the for the for the early stages. Importantly for the business Mike was was was been in Japan for many years he moved back to UK and he's he has a company at the. Bebra from campus and during lunch he met. VC from the. Robbie Woodman from the toolkit adventures and they started to talk about our company and then the discussion started so and the discussion is why don't you bring this company to UK and then we can we can find we can find this. This company so essentially so we have been moving from a company from trying to technology is a Japanese company. Essentially working in order to already have a commission or research and development of transferring know how to try and sign therapeutics in Cambridge with injection of venture capital so essentially we shut down here and start the new company, made all the documentation that is needed because always you need to have all the contracts or the documentation to transfer the intellectual property in the proper way so has been quite a bit of work and but we got to 5 million pounds of seed investments from insurance and which is a funny thing because the kid is a Japanese company and we started a company in Japan, and they both take the venture as you know, in us with the with the with the sub company in the UK. This Japanese company invest in UK from technology that are also coming from Japan showing that how much hostile and conservative environment really is negative for for for for investment and when you bring this in a different environment, it may actually work. And at the moment, of course, I don't know how it is Italy, but I know that there are various VCs in Milano area and and I'm sure that Italy probably is more is more is less conservative than this situation. Anyway, what was important is that the original, you know the that the funding was made on the data that we had already so actually actually working in the lab under collaboration agreement has been a good strategy for us. I don't recommend everyone to do this because it was very, very tough to do this. And now there is a transcendent therapeutics in and then I'm going to talk about the company in the next three slides so from that time, we are already three years later after this transition, and just I'm going to show you a little bit how the business has been developing in in this company and also from from the slide here I have received a modified from transcendent therapeutics, but essentially the company is focused on on developing synapse to take serious diseases that can be addresses by physiological production of endogenous protein. So, as I mentioned, it was started by, you know, by ourself that went to, you know, that brought the company in, in, in, in the UK. And do we do the talk at a ventures but also with we had the additional additional funds from the DTF, the measure discovery fund and the epidemics so essentially, we have the three three companies with the total investment of seed funding is about 13.5 million pounds so essentially this give us several, a few years to really move and started to really develop those RNA therapeutics. And the technology is there is the synapse so essentially, and also having the platform to modify and enhance translation of RNAs that are expressed in cells. As we said before, we want to increase the expression or any protein. And given that we will not touch the amount of RNA. And we think, and that this fine tuning of translation is, is a kind of more safe. So we don't have wrong. We don't have an expression in the wrong side because we targeted the RNA that is already in the cells. And, and also we modified translation we tune up to translation but it's not at the level that might be suddenly toxic because there is a hundred for the more protein, but we are, we are going to, you know, to 1.5 1.8 to two for the 2.5 which is quite often what you need to address some for me for some therapeutic application and we are also working on the delivery so can be a V vectors or we are also working to to make it short as a synthetic only going to die so we need to put a piece of the sign element and in the part of the 90 cents and within a 60 or 70 base base we have our artificial we call mini sign up or nano sign up. And also we are thinking about multi targeting as a, as a, as a product. So we started in a garage and or on a desk at home. And we have essential at the moment we have 20 people that are employed at the, at the TTX and there was a lot of RNA biologists visit them recently and get a talk and there was really a lot of science so I did not expect us so so many interesting biological question after that. And what actually very happy that the company can also speak that they can also also speak science. And essentially, the companies that is developing pipeline that are the potential to treat intractable diseases and ideas to go for the preclinical POC in 2023, mostly in of technology and in neuroscience and neuroscience come from Stefan or expertise because he has been focusing on on on on neuro the generation for many years and additional targets are on regulation, and the companies doing multiple partnering, but you have the picture of those two people here do you think that we are doing all of this, of course, no because we could hire a very, very strong team. And this is actually, you know, is a difficult thing if you're not in the right environment and you don't have the right connection and that will give you the credibility. This is a very important thing so you need to, you need to work on your connection to be able to hire these people like Ian who was, you know, he has been CEO of startups, but before he has been in various in various in in in in in pharma GSK and quite, quite a bit of experience but also, as you can see he's a scientist is a chemist in chemistry. The same is for Andrew, who is he's a has also a PhD and he has also big experience in in in from the basic science to GSK to AstraZeneca to various other social science, Anuj who has been, you know, again, he's been a CEO to various startup and meddling with again, a lot of, a lot of expertise and you need to construct those team and it has been quite, you know, it has been extremely important to to really hire them. So first, we were protecting the company by yourself and then once we find that the right team, we've been transferring and let them run as much as possible so here, a few more point to why we believe that we have advantages so for instance, gene replacement so you add a gene with gene therapy or a lot of RNA like Moderna, the potential issues that you cannot control how much you give, and so it's going to be difficult so you may have a lot of toxicity for over expression as well with the with the fine tuning of translation we may have some final regulation of, of, of, and so be much more physiological as a, as a response. There are other approaches usually give a down regulation, but we are probably quite unique, quite specific I would say to give up regulation. Modulation of up regulation is a key part of our of our of our of our strategy. Because functional genomics is moving very quickly, we believe that we can identify new targets, particularly thinking that targeting transcription networks targeting hubs that control expression on many genes and also with the, with the multi synapse. And here is the, you know, much more professional way to explain the technology so but you know I'm going to go through this just to remind you what we do. There is in the side DNA that produce RNA and and we and RNA is exported to the cytoplasm we want to target with the anti sense that the RNA on on the way to ribosomes to really produce more and to do this we again produce overlapping RNA that are connected to a sign element, this is as short as possible with the genes of interest and and and so of course there is quite a lot of research because there are many different sign elements that can work. Many different type of overlap that that are potentially working so that and we don't know yet if there are many that are tissue specific or self specific or work better in different system. There is a plant from the mouse that is the original one the sun element from the human human human element but we also have identified from Arabidopsis from the plant from the from the fishes and and that's what there is a cold water here that still awaits for that for additional and a very very specific applications. I have just a few more, you know, arguments why those why the technology is effective because it's a versatile against any protein. We can have viral viral delivery we can also multi targeted is accurate because the anti sense is for the sign up for the design up is very is very specific. And does not change the RNA level and all the protein as forms are up regulated and can and is also controlled. And as we said before, and actually what what I wanted to say is that of course once you have a professional team. You started to work also on the definition to attract other farmer other collaborator other other investment and again it's. It's important to stress that a good part of the preliminary data were made in collaboration with the with the with the with the funders lab. So the demonstration that we can improve Parkinson's disease in a mouse models by enhancing the translation of this gene so the Glya said rather than neurotrophic factors GDNF by using a sign up. So more protein and also in the street item and the affecting a phenotype is essentially a lower level here is the level of spontaneous movements, which essentially is addressing is essential seems to be important this most modern as a sign up to affect the to affect the phenotype of. Again this collaboration with from the lab of the start of the scientist the start of the company has been quite important. And I will just, you know, we will, as a company we we work, we work on targets like for a taxi in a free the free the taxi we need to bring this up GDNF and at the end also to produce more antibodies so here is a is a little bit of summary 20 people in the company 13 million funding is a platform the pipeline and so this is quite a quite a good to to see a company starting is a is a is a big pleasure. And actually, as if you're familiar with this, you will see that this is still quite early, and we are in the lead of optimization, but we are quite good shape to bring this into more close to any clinical trial, particularly having some diseases that that are not treatable and as a company we always think it, go from seed to serious a and serious be so here I will not know that those are predictions and as a company of course we are still, still, you know, still exposed to many risks, a little bit less than the in the early stages and there is a lot of work to do. As I said already and I would like to make the final consideration that, you know, this is the story of one company but different company will have their own, their own stories. And if you are involved in this you need to be very creative to, you know, from the creation of your network to to to all the steps that that will follow there is not no specific path for for success you need to you need to try. You have to, I would suggest that you start a company when you are very confident about the technology if you're not sure about who owns the technology you are not ready to to to start a company. You need to protect your your IP and you need to think in terms of intellectual property and the potential value of intellectual property, and how broad is the field that you can protect them. My story is a story for company that is not yet successful but there are important processes that we can already learn some lessons from this. Basic science is extremely important. You don't, I think that you cannot innovate if you don't go for the for basic science. People that started the company as a researcher have a very important role, and they should be allowed to participate so institutional rules and must be made that the scientists must must participate so there's always the possibility to have a conflict of interest that this is a part of the game. So if you want to play safe and avoid any conflict of interest you will have no innovations or just to be ready to have the scientists that will play in both sides. And starting your lab is important, but then move, but then once things get bigger you have to spin it out to keep your lab healthy continue to do the basic science and have the company to grow. So at a certain point you need to, to separate. You need to hire proper leadership that is essential for the next steps. And also to do this you need to have the connections and the connection is not only with your colleague in science but you need to really look for anyone that is involved in, in, in business and in, in, in, and having a very broad level of connection. So be careful, I would like to, I would like to stop here and happy to get any, any question from any question from you, and I, and I hope that the quality of the video and everything was fine.