 Okay well we'll give you a chance after Dr. Bennett's talk to ask questions of everybody. So now I get to introduce C. Frank Bennett, otherwise we call him Frank. He's a great guy. He is an interesting fellow. He has worked at a drug company since 1989, IONUS, and his focus has been on how can we use these anti-sense molecules to attack disease. And in fact, Frank was I think helped in many ways by not only the HDF's activities, but many other researchers' activities, but together with collaboration it was possible to actually show that they could affect things in animals. Now the other thing that's really important that I just wanted to tell you about is Frank just won the breakthrough prize. Now the breakthrough prize, many people think it's well it's definitely better than the Nobel Prize because it's three million dollars, but also because it really is defining people doing just cutting-edge work and he did not get it for the work on Huntington's. He got it for the work on spinomuscular atrophy, a horrible disease where children are born and start to become weak either as infants or young children and they lose the neurons going to their muscles and just become weaker and weaker until they can't walk, they can't speak, they are eventually die at about the age of three or four or five. It's fatal disease. He designed an ASO, anti-sense oligonucleotide that worked and there are now kids running around with that disease at six, seven, eight. He'll tell, he could tell you after his talk about Huntington's about this. It is a miracle and it shows that if this can work in spinomuscular atrophy, it's going to work in other diseases and he's already trying it. So that's what's so exciting and he is so awesome because he gives of his time to really work out how we're going to get this done for diseases that aren't maybe the most common disease in the world but the diseases that are extremely important to many people. So, Frank, please. Maybe we have to stop there. So, thank you very much. That's very kind and I do appreciate being invited to speak here today. It's very, a lot of fun to talk about some of the work that we've been doing and now we're starting to see some of the benefit of that work come to fruition and also I should acknowledge that when Nancy asks you to do something, she's the godmother and you never say no to Nancy. So it's a pleasure to be here. And so what I'd like to do is go into a little bit more detail about some of the technology that Dr. Tillman just spoke about and just to remind you that our genes and there's roughly 20,000 to 25,000 unique genes in the human genome are made into an intermediate molecule called RNA and one way to think about this is the genes, the hard drive of your computer where all this information is stored, it's transcribed into an intermediate molecule called RNA that goes away over time so it doesn't hang around very long and then that RNA is translated into proteins which are the scaffolds and the enzymes and what make our body function. And so this has been referred to as the central dogma of life is that DNA makes RNA makes protein and fortunately some of the proteins that are made are toxic and will cause a disease. They can either be genetically caused proteins such as Huntington that produce toxicity or sometimes the cell makes modifications on proteins that cause them to be toxic. And so as an industry and I've been working in the pharmaceutical industry now for 35 years our goal is really trying to identify drugs that will interact with proteins and there's really two classes of drugs that we have traditionally thought about. One that moved a little bit but small molecules that will bind protein and these are drugs like Lipitor, Asperin, we all take a number of different small molecule drugs that do bind to protein and impact the protein and we'll, sorry, go back one, will bind to the protein and modify the disease. There's another class of proteins that's really coming to the forefront now called antibodies and these are protein drugs themselves that bind to proteins and we all have antibodies that we generate but you can design antibodies to bind to proteins that will interfere with their function and that's commonly used now in cancer therapy. In fact, a lot of the big excitement in cancer right now is because of the antibody-based therapies. They've been used for inflammatory diseases like rheumatoid arthritis, the TNF inhibitors that you may have heard about are examples of this and so that's really a powerful technology for modulating disease-causing proteins in the body. We as a company are taking a little bit different strategy and what we're doing is to design oligonucleotides or drugs that will bind to RNA and remember there's 20 to 25,000 unique genes in the genome. We can design an antisense drug shown here that will only bind to one of those so we're only binding to one of the 20,000 genes so it's a very selective way of modulating function. Once the oligonucleotide binds to this RNA here, it brings in an enzyme that causes it RNA to be degraded and the net result is you don't produce the protein. So we're a little bit upstream of what most traditional drugs do and that we're not binding to the protein itself but what we're doing is preventing the protein from ever being made. So by reducing the amount of RNA, you reduce the amount of toxic protein that's being produced in the cell. And that's really the basis for the technology that we're working on. That may sound very Star Warsy and it probably does is that how in the world can you make all this work? And I can show you that we've been able to make it work. There are currently six approved drugs that use this technology today and they range from a drug to treat a viral infection that was very prevalent during the AIDS epidemic, a drug for cholesterol, the spinal muscular atrophy drug that Anne just mentioned a few minutes ago and I'll talk more about. And then a drug for another very severe pediatric disease called the Schoen's muscular dystrophy that's being used and then recently two new drugs have come on the market for targeting polyneuropathy. So it's a peripheral nerve disorder that antisense drugs are really showing a lot of promise for. And so what I'd like to do is just for a moment show you Spinrasa because I think it has a lot of relevance to Huntington's disease and Spinrasa is a drug that was approved about a year and a half ago by the FDA for cell in the United States. And so as Anne mentioned, SMA is what's called a motor neuron disease. So the nerves that innervate your muscle become sick. And one way I kind of use as an analogy is if you think about an electric cord being plugged into an outlet, those are your nerves being plugged into the muscle. And when these nerves get sick, they sort of fall out of the socket. So the nerve hasn't completely died off, but it's not making the electrical connection, so you're not firing the muscle. And eventually these kids will become paralyzed. So the disease presents as a spectrum, the most severe form of the disease is called type one SMA. And these are infants that generally present symptoms within one to two months of life. They start losing their muscle function. And unfortunately, they have a very short life expectancy of six months to a couple of years. And historically have been called the floppy infant syndrome today. There's another less severe form of the disease called type two SMA where they develop symptoms after six months of age and they're able to sit. So they do have some function and they'll live to their 20s and longer. But they are severely impacted by the disease. They have very severe contractures. They lose weight and don't have a high quality of life. But they do have a fairly normal life expectancy. And then there's the type three kids who again have the ability to walk. But as they start going through puberty and putting on a lot of weight, they stress out their muscles and they end up losing muscle tone. And so they lose the ability to walk later in life. And it really is a continuum. It doesn't really fit into a specific category. But it sort of gives you the extremes of what we're looking at. Unfortunately, these type one infants account for about 50% of the babies born will have this type one SMA. So that's the most severe form. And unfortunately, it's the most common today. So as mentioned, we developed a drug for type one SMA. And what I'd like to do, rather than show you a lot of numbers and graphs showing the activity of the drug, is actually show you a patient that was treated. And so this is Cameron, just to introduce you, who is a type one SMA baby. He was diagnosed about seven weeks of age and went on the drug at eight weeks of age. And so what I'd like to do is show you his progression while on the drug. And so if you could start the video. So this is four weeks old and looks like a relatively normal healthy baby, although he's not showing a lot of movement in his arms there. By seven weeks, he's clearly symptomatic. He can barely move his hands. And then we started on drug and so by four and a half months, so it's a couple months after starting treatment, he's beginning to show some strength in his arms. And you'll you'll see, you know, at 12 months, a little bit more strength, getting better. Sorry. And then this shows him at 16 months. So he's beginning to get some strength in his legs. And you'll notice that he's kids really don't have any neck control, your head's pretty heavy for most of us. And so lifting up your head is hard. By 20 months, he's beginning to stand. And this shows a picture at 26 months, a riding a horse. And by 36 months, he's riding a tricycle. So it really does show what this drug is done. And so just to remind you, this was what was anticipated that he would have become that really he would have been completely paralyzed by the time he's three years of age. And what we've done with treatment is I don't want to see we've converted them to a type two a less severe form of the disease, but it clearly resembles a lot of the symptoms of a type two SMA. And this should point out that he's still on therapy. And you can Google camera and SMA and you'll see the family post videos of their their child fairly frequently. He's now beginning to walk there. So really, we really don't know what what he's going to turn into and what the the future is in store for him. But it was much better than what the future was before this drug. And so that's why I'm personally excited about what we're doing in neurological disease is that I really do believe that we can have other examples like a spin rasa that we're going to have an impact on a very severe neurodegenerative disease. And so what I'd like to do and given the audience is tomer attention to Huntington's disease. And just to remind you, Huntington's, as a Dr. Tillman pointed out, is a disease where there's an expansion of the CAG repeat within the genome to produce this toxic protein. And generally, the way to think about is the toxic protein becomes sticky. And so you get these large aggregates that bind and stick together and they gum up the cell and the cell can't really deal with them very well. And they end up becoming toxic to the cell. And so I do think it's worth noting today. This is the 50th anniversary of the hereditary disease foundation. It's the 25 year anniversary since the discovery of the gene. And many of the people in this room, there are several scientists in this room that were instrumental in the discovery of the gene, including Dr. Wexler. And this is a large group of people. And one of the things that's really astounding is now that we have the human genome sequence, this took over 50 people 10 years or so to be able to identify this gene. Today, scientists are discovering genes that cause disease every day. And just with the expansion of the sequencing information that's out there, it's very common to pick up a journal or a science article about new causes of diseases. And it's a really testament to this setting the foundation for how we go about discovering genes. So just to take a step back, and I wanted to spend just a couple minutes to talk about the how we develop drugs. And so most of you are aware that the first step in this process really heavily relies on the basic research that's being done to identify targets and then understand the biology of those targets. So you have proteins like Huntington that was discovered 25 years ago. And we're learning a lot about the protein, but there's still a lot of mysteries and a lot more information that's needed to be found. But it gives us a drug target because we know the protein causes the disease. So the thought is if we can lower the protein that should have an impact on the disease. Once we identify a target, the next step is what we call preclinical testing where we'll screen for drugs that will bind or modulate the protein or RNA of interest and test those in cell culture and animals. And then once we get some confidence that the drug is doing what it should be doing, we'll advance those into clinical trials. And just wanted to highlight that there is a little bit more complicated than just going into clinical trials is there's actually three different phases of clinical trials. Phase one is generally the first in human trial. And the primary focus is on safety. So we're really just looking to see is the drug safe to administer to patients. You really aren't dosing long enough to see any kind of clinical effect, but it is where you have to start before you can run. A phase two study has a larger number of patients. And this is where you begin to start looking for signs of efficacy. It's still safety is the primary focus, but you are looking for signs of efficacy. And then phase three is the large studies. Generally, there are hundreds of patients, if not thousands, depending on the drug that you're testing it in. And that's where you really do focus is the drug doing what it should be doing to treat a disease. So it is, unfortunately, a fairly long process that this can take anywhere from, in the case of Spinraza that I just showed, that was a five year from here to getting the drug approved. Most drugs, that's actually a fairly accelerated timeline. Most drugs are five to 10 years and sometimes even longer. So this takes some oil to be able to get the final approval of a drug. And the reason I point that out is I want to put in perspective where we are in the process. So when we first started working on the Huntington, it was actually a project that we were working on with Don Cleveland and CHDI was a key funder of the work that we were doing. And the goal was really trying to figure out strategy. How do we use our technology to be able to target the Huntington gene? And so we had a number of different discussions and one of the strategies was to design an anti-synth drug that would bind to the Huntington RNA as well as the wild type Huntington RNA and bring in this enzyme that would end up degrading the RNA. And we call that total Huntington ASO and that it reduces both the wild type and the mutant Huntington there. Another strategy that we've been looking at is that we have heterogeneity in our genome. So even though we all have the same genes, there's subtle differences, generally one or two nucleotide differences between my gene and your genes out there. And with our technology, we can actually exploit that difference and we can recognize a single nucleotide change between this gene and this gene. And so we can design an anti-synth drug that would bind to the mutant Huntington but not the wild type and that was very attractive to us that we can cause cleavage of the mutant Huntington allele or RNA that's produced off that but not the wild type and sort of leave the normal amount of Huntington protein intact. The problem is that this would only treat about 40% of the patients out there with one drug and we could develop a second drug that would treat another 20 to 30% of the patients and another drug that would treat 10%. And before you know it, we'd have to develop eight or nine drugs to be able to treat all the Huntington patients in the world. Whereas this strategy allows us to treat all the Huntington patients throughout the world with a single drug. And so ultimately after a lot of discussion with our partners Roche on this as well as internally, we opted to go with this strategy as a strategy to take into clinical trials. And doing that, we found that there was really no difference in the activity that we saw in mouse models and there are a number of different mouse models of Huntington that I don't really want to get into. This is just one example of a mouse model. And what you notice is that if we started treating here with the antisense drug, the mice actually started getting better. We didn't just stop the disease but we improved symptoms. And again, you have to put this in perspective. It is a mouse model, it's not the human disease. But it was encouraging that the mice were getting better with treatment. And just to kind of highlight what this is, it's called a rotorod test, which if you can imagine, it's a log rolling contest for mice. And you're actually measuring how long mice can stand up on the log. And that reflects, you know, both their muscle strength as well as their coordination. And so it's commonly used in research, how long we do this. Actually, the researchers ought to have to do this as well to be able to administer the test. But it is, just think of it as the log rolling contest. And so you see that these mice are able to stay on the log a little bit longer than untreated mice with treatment. So that was very encouraging. And there were a number of other studies that we did that ultimately led us to start a clinical study. So what I'll share is just a little bit of the data from that first clinical study that we've done. This is, and I should have highlighted, these are all injectable drugs. So they have to use a needle. And in the case of Huntington, we're administering the drug into the cerebral spinal fluid that surrounds the brain at the base of the back. So it's basically a spinal tap. And I know that sounds horrible, but it's very commonly used and well tolerated by the patients that were in this study. And so the patients were given four doses of the drug. And it was called a dose escalation study. So the first group of patients were given 10 milligrams of drug. And there were about four patients that got that dose. We monitored them very carefully looking for any safety signals. And again, this is first time that we're ever exposing an experimental therapy to patients. So they're monitored for another four months after the dose was done. And look, make sure the drug was safe. Then the next group of patients got 30, the next group 60, the next 90, and 120. So it's a dose escalation study. It should point out that prior to dosing, because you are like you do have the needle in the cerebral spinal fluid, you collect a little bit of that fluid. And we use it for two things. One is that we measure safety to make sure there's no safety signals that are occurring that we can detect in cerebral spinal fluid. But importantly, as you'll see in the next slide, we're using it to document that the drug is doing what it should be doing. That is it's reducing the mutant huntington protein in CSF fluid, which reflects the mutant huntington protein in the brain. And so what we've demonstrated is a dose dependent reduction. So with the higher doses, we're seeing a lowering of the mutant huntington protein. Each dot represents an individual patient. And it shows the percent reduction that we see with the patients. And typical with the clinical trial, there is heterogeneity. Not everybody responds the same way to this drug, just like nobody responds to many other drugs. But if you look at the average, it was very encouraging that we were seeing this dose dependent reduction. Furthermore, we saw time dependent reduction. So first dose, second dose, third dose, you see it starting to go down more and more. We expect this to plateau off after four to five doses. So it's not going to just keep going down to zero, but it should show more robust reductions in the huntington protein than what we see today. And so what we're predicting, based upon a lot of modeling, is that a 40% reduction, which is here, would cause a 50 to 75% reduction in brain tissue. And so that's within the therapeutic range that we were seeing in the mouse models to produce the benefit that we saw in the mice. So we think we have a dose that should be effective at this point. So just as I said, this primary focus of the study was safety. And there were really no safety signals in the study. The drug was very well tolerated at all the doses. And none of the participants discontinued from the study. And in fact, we now have what's called an open label extension study. So all the patients who participated in the study were asked if they wanted to continue to receive the drug. And so they had to reenroll in a new study where they're getting the drug at the highest dose tested. And all 46 patients did reenroll. So they are, you know, further evidence that there were no side effects that would keep people out of participating in the study like this. And as I mentioned, this is a relatively short-term study. And so we never expected to see any kind of improvement in their symptoms at this stage. And we didn't. And so the thought is that you're going to have to treat for a longer period of time to really see improvements in symptoms of the patients. And so that brings me to what's next for this drug. You know, first off our partners Roche licensed the drug and, you know, supported doing the extension study. And they're about ready to launch a phase 3 study for this drug. So they're skipping phase 2. They want to accelerate getting this drug to patients as quickly as possible. And given the data that we had based upon the safety and the fact that we were engaging the target, that is that we were, the drug was doing what it should be doing. They're really starting a phase 3 study. And it has a, like all phase 3 studies, a fancy acronym called Generation HD that came out of this word. They pay people a lot of money to do this, I should say. But anyway, we're very excited to the study starting. And it is a fairly large study, 660 participants with 80 to 90 sites total in 15 countries throughout the world. So it will be a very big study. There are three arms to the study where patients will get 120 milligrams of the drug monthly, 120 milligrams every other month, or the placebo monthly. And it will, all the patients who finish the study will then have the option of enrolling into an open label study where they will all get drug, even the placebo patients will get the drug. As long as the drug is safe and no safety signals show up. So really, I just wanted to leave it here, I think, is that this is not the end. This is Winston Churchill's quote, I should mention, not mine. But really, we're at the beginning of the, it's the end of the beginning is where we are. So there's still a lot more work to be done. And just to kind of highlight and that Dr. Tillman talked about this, is that, you know, we feel that INS-HDTRX, which has now got a Rosh number, RG604, or for two, offers hope that Huntington may be a treatable disease. We haven't proven it yet, and so we still have to do that. It's important, because this is still very early, that we continue to invest in developing other therapies. You know, I suspect that we won't cure the disease. In fact, I'd be astonished that we actually cure the disease. So it really is to be thought of as a treatment. And to make the treatments more effective, it's important to keep investing in alternative treatments to go forward. And to do that, we need to find additional drug targets. And Dr. Tillman already talked about some of the modifier genes that have been identified, that HDF has been instrumental in helping to mine to get those. And ultimately, our goal is to continue with basic research to find additional targets, as well as clinical and translational research. We need to do both. And so with that, I'll skip this, because Dr. Tillman already talked about it. But I just wanted to thank the investigators who participated in the clinical trial. It was led by last year's honoree for the award, Dr. Sarah Tabrizzi. And you may have heard her talk last year. She's much more dynamic than I am. Sorry. And then finally, my collaborators that were really instrumental at UCSD, Dr. Don Cleveland and Holly Kordesiewicz. Sarah and Ed, Michael Hayden's group did some of the work. And CHTI was instrumental in funding, in particular Doug McDonald. And then the Hereditary Disease Foundation deserves a lot of recognition for getting us here and helping us along the way. Then my colleagues at Roshan and Ionis. Thank you. So I'd love it if people had questions for either Dr. Tillman or Dr. Bennett. So raise your hand if you have a question. Yes. Hi. Both of the presentations were fantastic. Thank you so much for explaining things so well to all of us. Dr. Bennett, I had two quick questions. One is when the strategy is to target just the mutant Huntington allele and not both alleles, why does the therapy only work on about 40% of the people? Right. So it has to do with, there's heterogeneity in these what's called single nucleotide polymorphisms, which are the single base change that occurs between all of us. And for a drug that targets a particular polymorphism, let's say it's a A, the other 60% of the population will have a G at that site and they won't be treatable. And so there is no single polymorphism that links 100% with the mutant Huntington allele. And so we're playing a genetics game that there was some diversity in our lineages that got us to where we are today and some of those we can exploit. But unfortunately for Huntington's it's not one that would be universal. We would only treat a subpopulation of the patients. Thank you for explaining that. Also, when are you expecting to start recruiting for this phase three and are the sites that will be participating already listed somewhere? No, the sites aren't listed. They're our partners Rosha are responsible for this so they're taking it on. They're interviewing sites as we speak to see which sites want to participate and then they go through a qualification for the sites to show that they have the staff and the infrastructure to be able to support the clinical trial. That's going on today. We expect to open up some sites in the U.S. by the end of the year and perhaps start dosing either, I suspect they'll start dosing patients at the beginning of next year, just given the holidays, but it's imminent. And there's a website called clinicaltrials.org that you can look on to and once there's a site that's. .gov, I'm sorry, clinicaltrials.gov. You can look on to and once the site is active they'll list there and then they'll also list the coordinator who to contact to, you know, if you wanted to participate in the study. Thank you. Any other questions? Yes. Hi, Dr. Bennett and Dr. Tillman. Thank you for a great presentations from both of you. My question is to Frank and Frank, if you had a crystal ball and I know you don't, but if everything went well with the ASO trial, when would you expect to see it approved? Yeah, so that is a crystal ball and again I just want to emphasize we're still very early. So there's lots of opportunity for things to go wrong because I don't want to overpromise, but the plan would be this trial would take probably three to three and a half years to finish and then once it finishes and you get the data, if the data is positive you would file with the regulatory agencies. I suspect given the need for therapies for Huntington's disease, the regulatory agencies will be very responsive and probably approve it within six months of filing. So generally it would take after we got the data, it would take three to four months to get all the data organized in a way that would allow filing and then another three to six months for approval if again assuming everything went well. So we're probably talking four years for a little over four years. Thank you and again thank you both for great talks. Could you comment, Frank, on what level of illness manifestations characterized the group that you preferably are going to work with this drug on? Right. And then maybe make a comment on if let's say hopefully things go well, how you then think about more serious people and perhaps people who don't even have the manifestations yet. Yeah, so this clinical trial is in early manifest HD patients that I need Dr. Young to explain to you what that means. But it's early stage patients will be in this trial and I don't know if you want to add some color to what. Oh, sure. Well, I mean, we have ways of assessing people both in terms of standardized tests of the motor system as well as standardized tests of the way we think and put together thoughts. And we know that there's a long period of time before you actually show the symptoms. Dr. Tillman showed that where things are changing in the brain, but you haven't got overt symptoms yet. I think what they want for this trial is to get people who've just fallen into those early symptoms where you can just start to see motor abnormalities and not later than that because then you wouldn't be able necessarily to revive dead neurons, but sick neurons. Yes. Yeah. And so the plan is to go both directions. Actually, you know, I think as Dr. Tillman pointed out, the future is really in prophylactic treatment. And so I really do see the presymptomatic treatment as a direction that we'll head. But first we have to demonstrate the drug has some benefit to patients. And then also I think we need to ask the question, what is the benefit in late stage patients? And so I see that happening. And then finally, there's a juvenile patient population that, again, I think we'll want to explore at some point. I have a question for Dr. Tillman. My daughter wanted me to ask this, so she's so shy. But you talked about there's other genes that affect the onset of Huntington's disease, which is the first time I've heard that. Could you just talk a little bit more, what are the genes affect the onset? There are, I think now four or five that have been, how many, Tom? There are five. How many? Fourteen. Fourteen. Fourteen. Which is, which is a lot, but it's going to give scientists tremendous opportunities for two things, I think. One is, what do they tell us about the biological function of the HTT protein? And that matters a lot to Frank, because we're here to develop strategies that actually reduce the level of both the normal size protein as well as the mutant protein. It's possible that that could be deleterious for a whole entirely different reason that you're losing the activity of the wild type protein. You know, there's so much that apparently is not known about what the normal biological function of HTT is. So I think these gene candidates are going to give us a lot of information about just the basic biology of what is going on. But then the really exciting thing, and I didn't emphasize this, so thank you for the question, which is that some of these, the variants actually prolong the period before disease onset. So those are the ones you're really interested in, right? You want the ones that are actually extending the time before symptoms occur. So if I were to prioritize those 14, that's where you would begin by prioritizing the ones that have the greatest impact on extension of normal function. No, I agree. It's very exciting, and it gives us not only us, but other companies as well, for the opportunity to have drugs that will impact the disease, and I think it's really critical. The one other thing that I would add, and this may be more than you wanted to know, but one thing to remember is that this protein is made in every cell in our body. Yeah, now it's pathological effect when it's a mutated form is in neurons, but we don't know much about what it's doing elsewhere in the body, and it would be good if we knew that actually. The second is that what we do know about the protein, it appears to be a protein that for better use of a word is kind of a scaffold protein. It interacts with a lot of other proteins. It may be a protein that moves them around in the body or in the cell inside the cell, but again, because we don't really know that, it's very hard to think about the impact of some of the kinds of therapies that could be considered. So these genes are, they're like clues, right? And it's wonderful to be able to have clues to function. I just might add that part of the structure of the workshop this weekend was to follow up on the exciting work that Nancy and David Hausman have been doing looking at modified genes in the Venezuela group. And they've come up with quite a few and we spent all of yesterday and this morning talking about ways we can extract those as drug targets. I want to just ask you to comment on something that evolves from what you said. And that is, so we're seeing modifiers that can alter the age of onset of huntings. What do we know about how many other brain diseases or other diseases may be subject to the same kind of benefit? Well, all of them are going to be. I mean, to the extent that certainly of all the neurodegenerative disorders, every one of them would fall into that category. Yes, in fact, for SMA, we've been doing a lot of work looking at modifiers for SMA. And we've identified, we didn't, but a group in Germany identified a couple modifier genes that when we target them with our anti-sensologos, we further augment the activity of nuisance. So it's clearly a therapeutic strategy that I think the industry and we're very interested in. And this is a question for you. So aren't there therapies that are either starting now to be tested in study participants to actually go in on some of the other chromosomes where they've found these SNPs or these small segments that actually do perhaps that increase the progression of the disease faster in certain people than others who have the mutant gene where they're actually trying to turn those off. I think I thought there were a couple that are actually involved in the cutting and they're screwing up the cutting of the genes. Exactly. So the issue here is yes, there are genes that delay the age of onset further than you would expect just based on the CAG repeat number. And also genes that shorten it and make it earlier age of onset than predicted. Now both of those are drug targets. Right. And we haven't started testing them in humans yet. But again, a bunch of people at this workshop this weekend have grants to look at these very issues in DNA repair enzymes that make it shorter onset, you know. So there's a lot of work and it's going to be very exciting. So I'm going to say look, everybody needs a drink. Yeah, we can talk to each other. This is great. Thank you.