Taysha Gene Therapies, Inc. (TSHA) Earnings Call Transcript & Summary

Good morning, and thank you for joining us today. My name is [ Fauci Kash ], and I'm an analyst at JPMorgan Selfcare Group. Before we get started, I just wanted to note that there will be no Q&A for the session. And with that, I'll pass it over to our speakers, RA Session, President, CEO and Founder of Taysha Gene Therapies; and Suyash Prasad, Medical Officer and Head of R&D.

Thanks, [ Fauci ]. Good morning, everyone. Thank you, guys, for having us this morning. I'm happy to be presenting an initial overview of our story. I'll just start with some forward-looking statements here. And here's a summary of the company really why we're so excited about what lies ahead for 2022, just starting with a couple of near-term value inflection points. We'll be reporting long-term durability and long-term safety data on our high-dose cohorts and our other therapeutic doses, from our lead program, TSHA-120 giant axonal neuropathy later this month. We'll also be presenting first in human data, which will be Hex A enzyme activity in the serum for our TSHA-101 program in GM2 gangliosidosis later this month as well. What's nice about this program is this is a groundbreaking first bicistronic gene therapy, bicistronic meaning 2 genes packaged into a single AAV9 construct. So we're quite excited about that. We'll also be presenting preliminary efficacy and safety data from our CLN7, Batten disease program at WORLD Symposium in February. So lots to happen here in just a few weeks, and we're quite excited about what lies ahead for the company. What really makes the company special is that we have a broad portfolio focused on monogenic diseases of the CNS stretched across 3 distinct franchises, neurodevelopmental, neurodegenerative and genetic epilepsies, and this has really been enabled by a groundbreaking collaboration with UT Southwestern. What really drives this company is our people, and we're led by a phenomenal gene therapy management team, in my opinion, one of the best in the world. As you can see, a lot of the members come from first-generation gene therapy companies AveXis, Audentes, BioMarin. And really, we've used that experience in order to really drive this portfolio at scale. We're also supported by an internationally renowned scientific advisory board, some of the best academic and clinicians in the world to really help make sure that we're on the right track as we execute on our clinical development. In my opinion, we have one of the most broadest portfolios in gene therapy. That's really appropriately staged. We have a number of programs in clinical development or nearing clinical development, approximately 5 and a number of programs currently in IND-enabling studies. As I mentioned before, our focus is on neurodegenerative diseases, neurodevelopmental disorders and genetic epilepsies. And as we embark on this year, we have 5-plus clinical data readouts across our portfolio. And again, across these 3 franchises, including one of the first programs in Rett syndrome which, in our opinion, really showcases not only our gene therapy platform, but also our unique novel design around payloads. And particularly in this program, which is TSHA-102, this is a self-regulatory feedback loop built into the transgene, essentially capping expression at a wild type level. So we're quite excited about what lies ahead as we embark on registration discussions, as we released high dose cohort -- high-dose data cohort from our giant axonal neuropathy program and first in human data in our GM2 program, CLN1 program and our SLC13A5 program as well. As you can see, our portfolio gives us the opportunity to address a large number of patients collectively where we have the ability to address approximately 0.5 million patients just in the U.S. and EU in long. And when you start to add in countries where gene therapy reimbursement is feasible, this number grows exponentially. But really, the way this works is because we have such a broad portfolio, but we're able to gain significant economies of scale. It starts here, and this is central to our scientific thesis is a focus on AAV9. AAV9 is the most studied vector in humans to date. It's been proven safe in effect across multiple indications in the clinic and now in the commercial setting with the approval of Zolgensma. We know how to dose it. We know how to scale it. We know how to design immunosuppression regimens around it, and we feel strongly it gives us our best opportunity to quickly translate these programs from the preclinical setting into the clinic and ultimately in the commercial setting in a meaningful amount of time in order to really address these diseases that have no therapeutic alternatives. The second piece of what we consider validated gene therapy technology is our scalable HEK293 suspension manufacturing process. We feel this is the right balance between scale and risk. It's been proven safe and effective across multiple indications in the clinic and multiple serotypes in the clinic. And we feel that it doesn't come with some of the potential inherent toxicities associated with other manufacturing systems, for example, such as baculovirus where there's always the risk of [ wholesale ] DNA ending up in the final presentation of the drug which is ultimately going to have an effect on increased immunogenicity, increased transduction efficiency. Obviously, there could be an effect on durability down the line and ultimately, again, having the drug, you lose its effect over time. And so for us, we think this is the right balance between that scale piece that we're looking to get but also the risk of a tox issue or an immune response issue. The last piece of what we consider validated gene therapy technology really centers around our focus on intrathecal route of administration. Doctors have been given intrathecal medicine for decades in an outpatient setting at this point in a safe and effective way across multiple modalities. It allows us to target the CNS broadly. We're able to evade neutralizing antibodies because we're starting on the right side of the blood-brain barrier in an immune privileged space. And to be quite frank, the proof is in the data. When used in combination with AAV9, we've seen phenomenal data, most notably in our own giant axonal neuropathy study, which was the first intrathecally dosed gene therapy study in history, which initiated in 2015 and was a groundbreaking study led by our scientific -- our Chief Scientific Adviser and Scientific Founder, Dr. Steven Gray, and our partners over at the NIH, Dr. Carsten Bonnemannn. So again, by controlling for these aspects of gene therapy or the gene therapy continuum, we feel strongly that you're able to increase probability of success and reduce overall risk. And what we're also able to do is get significant economies of scale because we're not changing things as we move in program to the next. The only thing that we innovate around is really the payload design. In some cases, you need to express 2 genes at a 1:1 ratio in order to address the underlying cause of the disease. And so what we'll do is we'll create bicistronic vectors. This is similar to our GM2 program. In some cases, you need a cap expression at wild-type levels in order to guard against overexpression associated toxicity. This is what we're doing in our Rett syndrome program with our miRARE platform essentially, a self-regulatory feedback loop that's responsive to the body's own down regulatory endogenous microRNAs. In some cases, we need to knock down the production of a toxic protein. So what we've done is vectorized microRNAs in order to knock down the production. This is what we're doing in our MAPT-associated [ telepathy ] program. And in some cases, we're just doing classic gene replacement similarly to what a number of our members of the team, including myself, helped pioneer with our work on Zolgensma. And this is what we're doing in our giant axonal neuropathy program, which we'll go through in more depth later. So again, by controlling for these variables, we feel strongly that we increase probably like success for each program, gain scale economies of scale across the board from a manufacturing, from a clinical development perspective, and ultimately, a commercial perspective, but still innovating around the payload and matching the payload to the biology of the disease. Again, this has all been enabled by our foundational partnership with UT Southwest and as you can see, Steve is on the right there and Berge is there with the tie. These are 2 of the most phenomenal clinical scientists, I think, in gene therapy. Obviously, Steve Gray comes with a long history of publications and groundbreaking translational research. He's really been active over the last, let's say, 10 or so years with a number of programs currently in the clinic, I think it is up to 7 programs in clinical development. And then Berge is the Head of Pediatric Neurology at UT Southwestern and really drives things from the clinical development and clinical trial perspective. And they colead the gene therapy program. Most notably, Berge discovered the MECP2 isoform in the CNS that also causes Rett syndrome. And so he's been a phenomenal thought leader as we look to develop our Rett syndrome program. As we look to scale up our portfolio of manufacturing, obviously, is top of mind, not only because of the scale and the consistency you need in order to drive a large portfolio, but many of the issues that we've seen in the clinic that's been driven by manufacturing. And we feel strongly safety starts with very clean, very pure product. And for us, really kind of focused on that empty to full ratio. This is something that has been driven home during our time at AveXis that we wanted to make sure it translated to our time at Taysha. We strive for our products to be 90% full in order to make sure that the viral load that we intend to give is the viral load that we're giving. And we do this through our scalable HEK293 approach, but also through this 3-pronged approach that we have laid out here. It starts with UT Southwestern that has small-scale manufacturing and of GMP capacity. We have a 500-liter GMP facility on campus at UT Southwestern in Dallas. We also have a 200-liter capability from a tox material perspective in a non-GMP way at UT Southwestern as well. And we've been fortunate to be able to tap that scale in that capacity multiple times. Catalent has really been a thought partner as we scale our manufacturing to clinical scale and commercial scale. Catalent is the only CDMO that's licensed to manufacture AAV9. They're actually an AAV9 commercial manufacturer for Zolgensma. Early on in the development of gene therapy and as we were looking to scale up -- commercially scale up Zolgensma, as we were building out the Libertyville facility many years ago, Catalent work side-by-side with us to actually transition the original hyperstack process to a commercially scalable process. And then ultimately, we'll be moving to our Taysha owned facility in Durham, North Carolina. That's a 187,000 square foot facility. It will be a multiproduct facility. It will have process development labs, the QC suite as well as release testing all in-house with at scale, we'll have 2,000 liters worth of capacity. That's enough capacity, we feel in order to meet our clinical and commercial demand, but we do have the ability to double that capacity to 4,000 liters in the near future if needed. And so again, by using this 3-pronged approach, we really have a flexible level of scale in order to support a broad portfolio. With that, I'm going to turn the call over to our Chief Medical Officer and Head of R&D, Dr. Suyash Prasad, to go through our our lead program, TSHA-120 and giant axonal neuropathy. Suyash?

All right. Thanks very much for the intro. And yes, I'm very happy to take you all through our 2 lead programs, AAV9 gene therapy for giant axonal neuropathy and AAV9 gene therapy for GM2 gangliosidosis, also known as Tay-Sachs disease or Sandhoff disease. So let me talk about GAN first of all. So GAN is a rare, severe progressive neurological disease. And the underlying pathological issue is a mutation in the protein gigaxonin. Now gigaxonin is a protein that's involved as part of the UPS, the ubiquitin-proteasome system in the cell. And what it does is it helps break down old denatured waste structural proteins. So in the absence of gigaxonin, there's no way of metabolizing the waste, old denatured proteins that would normally be recycled as part of normal physiological processes. And instead, the proteins build up in the axon. And you can see in the diagram on the right that this results in axonal swelling, which can be detected on a natural microscope. And in fact, in years past, this is how they diagnosed giant axonal neuropathy. Before you had genetic testing, you would take a biopsy of the nerve and look at the nerve fibers under the electron microscope. And you would see these giant axons. That's how it was previously diagnosed. Now what is the functional implication of this axonal swelling? But what it means is that the electrochemical transmission that travels down in there is impaired. So at the time, there's progressive slowing of this -- the electrochemical transmission down the nerve, we send results in the clinical phenotype of GAN, which I'll go into in a moment. Now it's a very suitable disease for gene therapy because it's a small gene, we can pack through the full length gene into the AAV9 capsid. You get very high transduction to the target -- or which is the brain and the spinal cord. And you only need a low level of expression to restore function. Perhaps what's most important is this is the first ever intrathecally dosed gene therapy. The first patient was dosed in 2015, and there's tremendous read-through to the rest of our programs. So this was a Steven Gray design construct. The study has been running at the NIH and in line with the commonalities that RA has already talked about, the fact that our platform is AAV9, is HEK293 mammalian cell suspension manufactured product and intrathecal dosing. All those commonalities are inherent in the giant axion neuropathy program. So there's a lot of learning from that and apply it to the rest of our portfolio. And also from a pathophysiological perspective, the fact that there is a waste product that is accumulating in a tissue, and we're administering a gene to try and encourage the recycling and removal of our waste product and allow physiological function to reappear, that's absolutely the same principle following for CLN1, CLN7, GM2 and many of our other programs. So -- it's really important to understand that there's tremendous readthrough from this program through to the wider portfolio of Taysha. Let's go to the next slide, please. And what you see on this slide is the clinical progression of the disease. So these children are born and they look fine at birth. And it's around the age of 2 that the parents notice something is not quite right. Now it could be they had slightly delayed growth of mental development at this point. But usually, what the first symptom is -- it's reminiscent of a sensory ataxia because the first function to go in these children is the sensation to the feet. So these children start stumbling. They can't feel the floor beneath their feet. They start walking with a very high stepping gait to avoid objects. They become increasing clumsy. They stumble and fall. And then the parents notice a progressive motor weakness that they develop a weakness in their fingers and their toes and the -- especially the hands. They get steadily and relatively rapidly worse. They develop central features, so ataxia [indiscernible], which is reflective of cerebellar dysfunction and the slackness. Usually these children worsen to the point where they need to be in a wheelchair because they lose their use of their legs around the age of 10. They end up going through Scoliosis surgery in their teenage years due to weakness in the core muscles. They're on the ventilator by the time they're 15 due to respiratory dysfunction as a consequence of neuromuscular damage. And then, sadly, these children usually die in the late teens or the early twenties. So it is a rapidly -- well, relentlessly progressive disease resulting in really awful quality of life, really poor clinical outcome, death in the late teens or early 20s, with no treatment whatsoever, so there's a huge unmet need here. There is a slightly slower progressing form, which has been described as a later onset form of GAN, which is not quite as rapidly progressive as the early onset form, still has a whole host of major issues in mid- to late-adulthood, progressive imbalances, problems of walking and some neurocognitive issues, [indiscernible] still issues, really hampers quality of life and is often mischaracterized or misdiagnosed as a form of Charcot-Marie-Tooth disease. And indeed, this particular form of Charcot-Marie-Tooth, Charcot-Marie-Tooth Type 2, probably 6% to 10% of these patients have a GAN mutation. And in terms of patient numbers and epidemiology, we're estimating somewhat conservatively that in the U.S. and EU, there's about 2,400 patients with this condition. About 1/4 of them will have the early onset form of GAN. Next slide, please. So the clinical trial, as I say, started in 2015, 14 patients have been dosed. I'm going to share the data from the initial 3 doses. There are 4 dose cohorts, and we've shared publicly the first 3 dose cohorts, which I'll go into in a moment. Two years prior to starting the interventional study, the principal investigator Carsten Bonnemann, who's a very well-known and esteemed neuromuscular, pediatric neuromuscular expert of the NIH, started a natural history study, the first ever natural history study to look at GAN in detail, 45 patients have been enrolled and published. There's actually close to 50 patients that have been enrolled in the study now. And the key outcome measure -- a whole host of different outcomes measures were looked at in this particular study, but the key outcome measure was the MFM32. And I usually describe this as -- if you're familiar with the SMA story, the CHOP INTEND for the infants, the MFM is the CHOP INTENDER for the slightly older patients. So it is validated from children 2 years of age and upwards. It's a well-known scale, clinicians are very used to it and regulators are used to it. There are 32 items, each of which are rated by an expert clinician or physical therapists. It's been used in Duchenne, SMA, a number of different muscular dystrophies, cerebral palsy. And it's recognized that a 4-point change in the MFM32 is deemed to be clinically meaningful. So 4-point improvements is a clinically meaningful improvement, a 4-point decline is a clinically meaningful decline in function. Next slide, please. Now what you can see here from the natural history study, the graph on the right shows the MFM score plotted against the page. Now the score -- scale goes from 0 to 100, I'll say 32 questions. This was 0 to 3 for each question. Then they've converted to a percentage and a drop in 4 points is deemed to be a clinically meaningful drop. What you see here is that children with GAN seem to drop their MFM score relatively consistently from about the ages of 5 to 15. So they drop by about 8 points per year. Don't forget, a 4-point change is deemed to be clinically meaningful, but these children drop at about 8 points a year. And they could drop by 8 points a year from the age of 5 where they started out at the score of 90, 95, or if they're 10 and start at the score of 60, still dropping at this 8 points per year. Now to give you some context, a healthy child would score 100 on MFM32. By the time it drops -- the child drops to 70, they need a walking aid to help them walk. And then by the time they drop to 55, and with GAN, this will probably take another 2 years after they've started using a walking aid. By the time they drop to about 55, they need a wheelchair. So this scale is very closely correlated with functional outcome. Next slide, please. So that's the natural history data. In addition to the MFM, there are many, many other parameters looked at, we just want to focus on the MFM32, which is the primary endpoint. This is the construct. You can see that it's the full-length human gigaxonin gene, associated with a JeT promoter. And the JeT promoter is a relatively small promoter. It's synthetic. It is a ubiquitous promoter, which means it expresses in all tissues, but it is a moderate strength promoter. So the risks of overexpression are reduced from user and moderate strength promoter such as the JeT promoter. This promoter and full-length human gigaxonin gene is wrapped up in our AAV9 capsid and the drug is given intrathecally. We do have orphan drug and rare pediatric disease designation. And as I say, Steven Gray design construct and the clinical trial has been led by Carsten Bonnemann in the NIH. This is a study design. And what you can see here, if you look at the right-hand side of the slide, you can see that there are 4 dose cohorts. The lowest dose is [ 3.5E13 ] total vg, and then the doses go up overall, of course, of a lock up to [ 3.5E14 ] total vg. Now I want to make a couple of points there. First of all, and this is a really important point to appreciate and understand which I know many of you will understand but some people don't fully get the nuance there. We are dosing total vg. You'll see that in the actual slide, 3.5, the maximum dose is [ 3.5E14 ] total vg. This is different to a systemically given gene therapy, i.e., a gene therapies given into a vein where you dose with vg per kilo. So if you think about it, if you're giving [ 3E14 ] vg per kilo into a vein to a child who is 8 years old and weighs 30 kilos, the total viral load is very high. That [ 3E14 ] gets multiplied by the 30 kilos of child weight. So you're getting close to [ 1E16 ] total vg. So it's important to understand that you're giving actually much less dosage of -- much less viral load when you give a drug intrathecally. But it's a low dose in terms of systemic exposure, meaning the side effect profile is likely to be more favorable, but it's a high dose being target-specific into the brain and spinal cord, which were given the drug intrathecally. And how we give the drug is actually seeing the images at the bottom of the screen, you pop a needle -- a spinal needle into the base of the lumber spine. You drain out a few mills of [indiscernible] spinal fluid. You then slowly infuse, usually about 10 ml of the drug. You have the child resting on that back and head down on one side and then you rotate them to the other every 15 minutes. And what this does it encourages CSF flow down towards the brain and spinal cord. And we find that with this approach, we get very nice by distribution. And you'll see surely some very beneficial clinical improvements in these particular patients. The final point to make is that we cover with our standard immunesuppression regime of prednisolone and sirolimus. Sirolimus is also known as rapamycin. So we give 6 months of prednisolone, 4 months of 1 milligram per kilogram per day, and then we tail off over the next 2 months. So the child is up, and spared by 6 months, and we get a full year's worth of rapamycin. We titrate it to serum level. So we're being very precise about the amount we give. Rapamycin is a very good, well understood T-cell modulating drug. And this is really to help prevent any T-cell inflammatory matters that sometimes happen when you give a gene therapy. And on that regime, with an intrathecal dose and the dose range we're giving, we've had a very, very good safety profile with this particular program, and I'll touch on that in a moment. Okay. Let's get to the next slide. This slide, the slide on the right shows the effect of a medium-low dose and the medium-high dose. So you'll see this natural history drop of MFM32, pre- and during gene transfer where you see the vertical line at time 0, that's when we dose drug. The medium-low dose is in the blue and the medium-high dose in the green. And what you see is this drop immediately stabilizes and we get a flat line, so no further decline in the trajectory of these patients. And I'll remind you that Steve been going since 2015. So we have many, many years' worth of long-term efficacy, long-term safety and long-term durability data. Let's go to the next slide, please. Now this is to give you a bit more granular view. This is why you're looking at the patients as individual plots. And perhaps the best patient to focus on just for the purpose of example, is the lowest producing -- the lowest performing patient on the MFM -- on the MFM32 at the medium-low dose in the blue. So you see this child drops from about 60 to about 36, 37 prior to treatment. As soon as they are treated, that decline holds, and it stays stable over the next 3 years. So this translates to an 8-point change, an 8-point improvement in the trajectory over 1 year, 16 points over 2 years, 24 points over 3 years. So really, really dramatic clinical change to the trajectory that these patients would otherwise have. This is clinically meaningful and demonstrates clear disease stabilization. So when you look at the data, you've got clear stabilization of disease at the medium-low and medium-high dose. And with the high-dose data yet to be shared. You've got dose response, you've got long-term safety, long-term efficacy and long-term durability data, all of which really going to be very helpful as we enter our phase of regulatory meetings, which we start in a matter of weeks. Next slide, please. We did a secondary analysis using a basin approach to really performance sensitivity analysis and our credibility increases through the data. Three things now about the basin approach. And the first is that it's increasingly being used by regulators over the past 15 years or so. It was not so much in favor previously because it needs a lot of complex modeling and computational techniques aren't quite there yet, but they are now. So increasingly used by regulator, especially in these diseases that have a very small number of patients, but a very big change on the clinical endpoint. Secondly, you end up with a probability state as opposed to p-value. So this is important. And if you look at the table in the bottom right-hand corner, what you can see here -- and it's a little small on the slide, I apologize, but what you can see here is that the medium-high dose of [ 1.8E14 ] total vg, the probability of any slowing of disease is 99.9%. So every patient will have slowing of disease at this medium-high dose. The probabilty of a clinically meaningful slowing of 50% or 4 points or more is 98.3%, so virtually every patient is going to have a clinical [indiscernible] effect at the medium-high dose. And don't forget we've got the high dose yet to come. Next slide, please. In addition to [indiscernible], this show another endpoint. Now the NIH did a lot of great work doing a breadth of endpoints. And as you know, the regulators really appreciate the totality of data looked at many different systems and functions. What we see here is visual acuity. Now -- it's one of the most troubling, upsetting aspects of these diseases when children lose that vision for the parents because each child loses their ability to speak, to hear, to move. And when the vision goes, it's the last way the parent is able to connect with this child. And then that goes. And from our numerous patient workshops that we run really trying to understand the patient perspective, we realize the real importance of this. What you see here is that there's a lot of scale here, which is visual acuity, it's a bit like snow and chart when you get to the doctors for an eye test, but it's a more research-focused way of doing it. What you see here is that score 0 is normal; 0.3, you need glasses; 0.6, you have significant visual deterioration; 1.1, 1.2, you're blind. Apart from an outlier, every patient is worsened without their vision. As soon you treat, that visual loss stops. So once again, you show really clearly an arrest of the loss of vision. And this is backed up -- I don't have a slide here, this is backed up by the OCT data we produce. So looking at the wrap on nerve fiber via thickness, where the loss of retinal lobe is stabilized after treatment. So really powerful data and we shared this with the group ophthalmologists very recently and that are very impressed. In terms of anticipating next steps for TSHA-120 for GAN, we will be sharing our high-dose data before the end of January publicly. We have initiated manufacturing and commercial roll of products. We have our first regulatory retail coming out shortly. And we'll be updating you on an ongoing basis on the outcomes of those regulatory meetings, but the intent is to discuss a pathway to regulatory approval for this program. Okay. Let's go to our next program. We have about 8 or 9 minutes left. So I'll go relatively rapidly. This is GM2 gangliosidosis, also knows as Tay-Sachs disease or Sandhoff disease. Now -- the -- as a less understood disorder, which is generally very, very severe. The vast majority of patients were infants [indiscernible] die at the age of 3. The underlying pathology is due to mutation in the enzyme known as ß-hexosaminidase A, abbreviated to HEX A. In the absence of HEX A, you've got a build up of a substrate in the lysosomes to the cells. This substrate's known as GM2 gangliosidosis. Now the GM2 gangliosidosis should be converted to GM3 in carrying down the pathway, but because there's a block in the enzyme here, you get no GM3 and very high levels of GM2. And that -- those high levels of GM2 build up in the lysosomes. The lysosomes swell, they rupture. They cause neuronal tissue death and then damage results in the clinical phenotype of GM2 gangliosidosis, also known as the Tay-Sachs disease and Sandhoff disease. The reason there are 2 separate diseases because of the Hex A enzyme, ß-hexosaminidase A is comprised of 2 subunits, an alpha-subunit and a beta-subunit. Mutationally, alpha-subunit gives you Tay-Sachs disease, mutational beta-subunit gives you Sandhoff disease. But essentially, they are the same diseases. They both result in its lack of functioning heterodimer which then results in the lack of ß-hexosaminidase A and you get the buildup of the GM2 gangliosidosis. So rare disease, about 500 patients in the U.S. and EU, but likely there's a larger number of adult patients around who has yet to be diagnosed. Importantly, underlying levels of baseline enzyme very closely correlate with clinical phenotype. So the infants of less than 0.1% activity, they die at around age of 3, the juveniles, 0.5% activity, they die around the age 13, 14, 15. Still an awful disease. The adults tend to live a relatively normal lifespan with significant neuropsychiatric issues, 2% to 4% activity. And even if you did 5% to 10% activity, you're asymptomatic and essentially healthy individual. But one thing to notice here is that a small amount of enzyme goes a long way. So small increases in enzyme result in quite a dramatic improvement and lifespan. And so the bar is relatively low in terms of replacing the enzyme here. Next slide, please. In terms of clinical phenotype, as I said, the infants are pretty sick, and they die around the age of 3. This is the construct and this is very interesting because it's the very first ever bicistronic vector to the clinical development. What I mean by bicistronic is that there's 2 genes in 1 gene. The gene alpha-subunit, HEXA, the gene beta-subunit, HEXB, joined by a peptide linkup, and wrapped up in the AAV9 as sub-complementary capsid. Now this is really important. So we give the drug intrathecally. Drug travels the brain cells, DNA pops out, alpha-subunit and beta-subunit are produced and -- the most important thing is to realize the alpha-, the beta-subunits being produced in a 1:1 ratio because they're driven off the same promoter. So you then get the functioning heterodimer produced as efficiently as possible on a cell-by-cell basis. And this is really important. This is going to be very important in terms of ensuring we get as maximum efficiency of the transduction process and also maximal efficacy as much as possible. I have 3 slides of animal data. The first is a survival slide, and we've given 3 doses of our construct in these animals. What you see here in the Sandhoff mouse model, a knockout model, in which we dose several weeks after birth. So we allow the mice to actually become sick before dosing. This really puts sort of pressure on the test as opposed to dosing [indiscernible] mice will always do very well. And we see here, as you go up in dose, you see an increase in survival. Next slide. In addition to survival improvements, you can see functional improvement, i.e., distance traveled [indiscernible] also goes up as you go up in dose. And it actually normalizes at the highest dose amidst in this particular study. And this is reflected in the next slide by a nice reduction in GM2 ganglioside. I've already talked about the fact we're trying to reduce the amount of GM2 ganglioside accumulation and increase GM3. What you see here is a very nice dose-dependent reduction in GM2 ganglioside. This is a clinical trial once again, intrathecally given covered environment of expressive regime at a high dose delivered to the brain and spinal cord, [ 5E14 ] total vg. So a high dose [indiscernible] to the brain and spinal cord, the low dose in terms of systemic exposure. We've started recruiting patients and intend to share biomarker data, specifically [indiscernible] in the serum and some GM2, GM3 data before the end of the month. Next slide, please. So in terms of outcomes, I'll just briefly go over these and hand over to RA for a final closing comment. We've got our GAN high-dose data, long-term durability data and then our preliminary safety data and HEXA data from GM2 coming out in January. CLN7 will be presented at the WORLD meeting in the middle of February, and that's another one of our programs that we're very excited about. We'll be sharing clinical biomarker data from CLN1 disease program in the middle of the year. And then we'll also have clinical data available for 2 additional programs, the Rett syndrome program and SLC13A5, the very first gene therapy for genetic epilepsy before the end of 2022. On that note, thank you very much. I'm going to hand over back to RA for final closing comments.

Thanks, Suyash. And again, thanks, everybody, for their attention this morning. Really, we looked at 2021 as kind of a building year, a foundational year for Taysha as we were coming off of the IPO and founding the company in 2020. And really, I think the fruit of that work is going to really show this year as we have a number of clinical data readouts scheduled starting this month, but really continuing throughout the year, 6 in total. And so again, we really appreciate the time today. And hopefully, we shared with investors our enthusiasm for the platform, but ultimately our goal of eradicating monogenic CNS disease. So with that, I wish you guys a good morning, and thank you again for your attention. Thanks, guys.

Bye-bye, everyone.