 Good evening everybody also from my side. Thanks to Vika for the kind introduction and today I'm here to speak to you about gene therapy Which is a revolutionary medical approach that has been around in the field for over almost two decades more than two decades But just now is reaching the point where actually can reach the wider public First of all before going into the technique I want to ask you and see which audience we have here tonight Who of you actually have heard of gene therapy? Please raise your hand. Oh Okay a lot Actually, who of you knows how gene therapy works from a biological point of view Okay, this makes me a bit safer that I will not bore you too much and for those of you already know I hope you get some new knowledge. It's important I think first of all to go through the definition that the geneticist gives to this approach which is Replacing or correcting a mutated gene within the cells affected by the disease with the aim to treat or prevent the disease So basically curing disease with the help of with the help of DNA and genetic engineer Before going into concept that are fundamental to get what gene therapy is that is Mutation and gene. I was just thinking how to link a bit more with our daily life also for those of you who didn't raise the hand not even the first time and Actually something that always we actually are much we listen a lot about genes Modification and some just in popular culture with movies for example I think one reference that all of us knows is X-Men, right? So suddenly there is a future. Well or past or a present according to the movie You refer to in which suddenly some genetic mutation appear in these people and then they acquire superpowers Well, this is quite unrealistic But still gives an idea for something that I think is a bit more precise of what gene therapy is Or could be in the future even if still far away, which is Gattaka, which I think is a really nice movie at the end of the 90s in which basically there is The possibility in a soon future to modify the DNA of your kids before it's born in a way that you create a genetically perfect Individual but this leads the genetically perfect. I mean that it will not develop disease like all of us are susceptible to But then leads to a bias in society between those that actually do not want this technique and those that actually apply creating perfect human beings and those that are not which is means like us I Believe And then so now we get like what actually in the movies we may think about genes and mutation But what actually really is for biologists? First of all, this is an organism like us human being and all of us have in common that we are all made by cells You know and all of these cells basically carries an information that makes them unique, you know I mean common in a way, but also unique in their functions so that we have different cells in our body and This information is the DNA if you allow me the comparison is like a book All the book contains a lot of characters that all together bring like a specific information Specific knowledge that makes the specifics this cell unique and if we look into details Actually DNA is made like books is made by letters that all together create You know per se these letters doesn't have much of a meaning But then when you put this letter together you create a word Which is a functional like a functional piece of this DNA that is a gene and this gene code for a protein a Molecule that makes if you sum all this protein within a cell makes the cell specific for its function So that's why we have brain cells That's why we have cells of the eye because there are specific genes in these cells that get activated and makes the cell specific for the function It's important to remember that constantly throughout our life. We grow we age will we get wounds and we need to regenerate the cells right and This means that we need to copy this information along our life many many many many many many times and You have to keep in mind if you keep if you think about the numbers that we have trillions of cells in our body Millions of cells that daily are in you when you lose skin or hairs and each of these cells contain a code Sequence of letters that is 3.2 billions So if you're better than me and making math you can imagine how many times we need to copy this information and this means that like and if you think like How many times you need to copy then how many chances of actually making a typo or making a mistake when this happens? Actually, sometimes we these mistakes in can happen in a portion of the our DNA or our Book that does not have an effect on our life and sometimes it's actually what make us different Why I have brown eyes and you have blue eyes But then for in sometimes it also push for evolution But if it happens inside of one of these words that this can create a mutation that can affect the function of the protein And so leading to a protein. This is no more functional affecting at the end the cell function And if you think if I will leave the analogy of the book now with this last example Just saying that between these there is just one letter different, but the meaning is definitely not the same But then if you if you copy these many many times, you know, we need to replace I'm glad you liked if you need to Copy this information many times and there is a mistake This means that with the time we can create an organ that is no more functional And this is why all our organ in our body is susceptible to disease Now I for introducing introducing to you the core of my topic, which is gene therapy I want to focus on a specific organ, which is the immune system or the blood derived cells You will see soon why So the blood cells are one of the peculiarities of the cells of these cells is that they reproduce all our life is one of the cells They proliferate or divide the most their home is actually in the long bones of our body so and turns and the spine and the femur and The home is called bone marrow and inside here. You can find this stem cell Let's say that can proliferate can Generate the red blood cells the one that carries oxygen throughout our body and lymphocytes What is important about these lymphocytes or white blood cells is that they protect us from but virus bacteria So we are we are able to cope with the flu because of those cells. Otherwise we may die So if you imagine that there is a mutation that affect one cell like this, you can imagine the output Well, actually, that's the case of the first disease that has been cured Back to the 90s or the first approach of gene therapy has been made which is called Addening the aminase severe combining with efficiency or other shit for friends Well, it's quite a long number. We don't need to focus on this But what I want to tell you is basically that it's a mutation in this protein called other that now You know what is a protein that comes from a gene Which means there is a mutation a type on the gene coding for other and then this protein is involved in cell division So basically these cells that they proliferate like crazy. They divide like crazy when a bacteria comes to your body They are not able to survive So we don't have this anymore part of the body that is called immune system or adaptive immunity And so basically the kids it's a really rare disease one out of 100,000 the kids die because of immune system Functioning so it comes a flu and the kids die How they could survive what were the therapies? You may have heard of these kids affected by the disease as bubble kids because the only way available to the 90 90 to survive for those kids was actually living inside a shell Protecting them from the outside environment so that they couldn't interact with people they couldn't touch and everything was filtrated and of course I'm speaking about the kids that were affected in countries that had this technology available and The few therapies available was bone marrow transplantation, which is still nowadays an option so the bone marrow as I mentioned before is the home for these cells that we have in our body here here here and But this is available only one fourth of the case because of match needed another therapy available was Taking these protein from a cow and putting in the in the kids But this was with time was becoming inefficient and then those kids were not able to survive because of this Then in 90 90s after more than two 20 years of speaking about this approach here It comes the first gene therapy trial 1990 how does this gene therapy finally work? Let's have a look So what you need to do you need to take the cells From the spine of the patient So meaning this bone marrow and then you have the cells that carries this mutation, right? If we think about other Then what you need to do you need to insert the therapeutic gene So the gene that I mentioned you before is without this type Oh, and you need to insert inside the cells in the way that those cells are actually they can actually Produce produce the correct protein then what you need you expand the cells in a lab That's why it's called ex vivo gene therapy because you take something outside of the body You work on this in a lab and then you put it back into the patient to do put it back in the patient often You also need to do some chemotherapy to kill the whole the sick cells to allow the new ones to be to get to be grafted So this is the general approach for gene therapy Was clear enough But one point that I think it's really cool to raise is this about using a delivery vehicle because we need to carry inside the cells this correct gene and one of the most I think fascinating part about this is that actually what we use to carry This or what one of the things we use is actually a virus So you may think okay virus are dangerous, you know, which actually are So how come that someone thought to turn in this force into friends, let's say Well, just you just need to see about the biology of what a virus is a virus is nothing But an envelope that contains pieces of information genes so pieces of DNA but the per se they cannot survive they cannot replicate they need to find a host cell and To find this host cell is usually one of our the cells of our body of other organism And then once inside they can use the machinery belonging to the cells to replicate and survive and spread But these often for the cell is pathological is created disease because the cells die you'll get recognized by the immune system So what the scientists thought back to the time was why don't we take this ability of a virus to infect the cells? This is HIV virus you take out the bad things from it and you put inside what you want to be expressed the correct gene Other in the case I explain you then you infect the target cell and then you correct it So this is the general approach Which was started in the 90s But still nowadays is actually one of the most used one because you have many different virus HIV Herpes virus adenovirus that are used the motive after modification to cure people There are also others that I don't I'm not focusing now I just want to mention this approach that you will hear a lot in the news in the next 10-20 years because it's kind of a breakthrough that will speed up much more this gene therapy Anyway till 2015 at least most of the clinical trial Testing so gene therapy on different disease was actually made by virus So where are we now? 1990 first gene therapy for this disease and But we have to reach 2016 to get the first drug approved for this disease Which is anyway the second drug the poor in the world using gene therapy So we have a gap of more or less 22 years Well in the 90s there was a lot of excitement Thousands of clinical trials start in using this technique, but then in the early 2000 Some tumors appear in some patients undergoing this clinical trial and also some died So there was a step back in the research and then we spent the last 15 years trying to improve the situation With safety studies new regulations and vector improvement to avoid this from happening And I believe that now we are at the point where we know much better also because of the technology To finish the the topic giving you one last concept that I thought that you may think okay You know we have a gene therapy for other sheet 25 years billions and billions of Dollars euro whatever invested in this approach, but then we cure you know one kid every 100,000 Every life matters. Of course, maybe there were other ways Can I ask how many of you have heard of other sheet before then tonight? Okay, well too. Okay, this was more successful How many of you actually know one of these disease? Please raise your hand if you know at least one Okay, everybody. So this is the future of gene therapy All of these disease and many more are actually under clinical trial for gene therapy Most of it are actually cancer research cardiovascular infectious neurological ocular disease So this means that there are over 50 millions of people affected by those pathology every year that are potential target for gene therapy So I hope you see as I see also that great potential inside this approach is medical revolution. Let's say So my take a message for you is that it's fundamental to share knowledge to share Your expertise with people that are actually not from your field because I think gene therapy Resemble a beautiful example of this because here we have experts in virus that share their knowledge with stem cell biologists So studying how lymphocytes get Affected with the genetic engineer or molecular biologist. So like exactly, you know That's why I also wanted to come here to discuss with you because I may have get Not about gene therapy, but nice inputs afterward and then they came together creating this beautiful approach That is gene therapy and that allowed these two girls that were the first one treated with gene therapy in the 1990 to live a totally Normal life while they would have died by the age of four Thanks. Oh Thank you very much and Luca now we have time for some questions Also be aware that I will repeat the question after you say it Don't be surprised so that we can hear it clearly on the live stream and in the videos. So who has some questions There is a question. Yeah, please Yeah Let me repeat the questions first. So the first question was which of the gene editing methods You think is the most efficient currently from what exists and the second question is Since there were some problems in 90s, there's quite unlikely that the ethics committees will approve the new adenovirus associated The denoviral it's adenoviral treatments. So what's the alternative that we can then suggest, right? Okay, I think you really know a lot. So I Hope I don't say something wrong For sure regarding the set the first question. So what could be the future of this? Which of these editing? Possibilities could be the future I think is indeed cast 9 that I mentioned before which now I cannot speak about this topic Which would require one hour just but it's definitely one of the biggest breakthrough And I'm sure they will win over prize in the next years for this and anyway This is a cast 9 in is indeed a technique which is much safer much more precise and Much faster and also cheaper. So it looks perfect But still a bit to work on then the one of virus But for the moment to the technology available and to the clinical trial that we are still I think some kind of Virus are the legible and it always depends on the disease that you want to target Regarding the second question so This was quite specific for the death of that that happened because they in fact They told you we use a virus to cure modified virus to cure people, but the the people that got this virus was actually Reacted to these and died because of the vector itself These I don't think I we can have a look at the graph of the different virus use And you can see the adenovirus are still the top use till 2015 So I guess I'm not an expert on how they modify them to make them less immunogenic probably with the Specific with a set of type. So if there is still 20% on I guess these are these means that they are still using quite a lot Okay, thank you. Yes, there is another question, please so I'm curious about the mechanics of it, so if you remove the Virus the car of it the bad thing and replace it with something good Also Yes, the question is is it possible to create a virus which doesn't have the harmful parts But still can replicate and replicate the good parts that we want to Transport transport well by law It's actually one of the few regulations that has been made Internationally is that if you use a viral vector the point is that viral vector cannot Reproduce if you want to use it for gene therapy because of safety issues. So I don't think this point will will be Used that you would rather use the ability of the you would rather target stem cells with the virus so that and then with Something that integrates in the DNA so that they can carry to the daughter cells because this would be much more effective What you mention it exists for other kind of approach for cancer But I don't think now I should go so much into details We I can tell you about it later because it's more specific hardcore biology That I don't know if everybody's interested but what you mentioned it exists But for other purpose more for cancer research with a different I spoke about ex vivo and this about in vivo gene therapy So it's another side of the approach Okay, more questions you have Yes, please So the question concerns the gene therapy or kind of a gene therapy that is used to Induce immunogenic reaction to the cancer and what can you comment on that? Well, this is actually this exist You're kind of ready gave the answer to your question because it happens It's made and it connects a bit to what he said So that's a totally part of gene therapy in their broader meaning of modifying a cell to cure something It's just the way of action that is different But it's totally done to take lymphocytes modify them to target a cell especially depends on the kind of tumor But also guys if you have more basic question, they'll be scared and ask because these are really cool question But they are hardcore biologists So somehow rise up the plank in the beginning, but yeah guys You I suggest that with the more basic questions than you discussed in the break now We need to move on to the next talk. It's not that I don't like the basic questions. This is not the case I just don't want our next speaker to wait. So please Thank you and look again and please approach him in the break to ask more questions