Good morning, everyone. Thank you for joining today's webinar. Today we plan to review clinical data from Editas Medicine's EDIT-101 program, which is currently being used in the phase I/II BRILLIANCE trial for the treatment of CEP290 related retinal degeneration. As a formality, there may be some forward-looking statements during this webinar. Various remarks that we make about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the safe harbor provisions under this Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factors section of our most recent annual report on Form 10-K and our subsequent filings with the SEC. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. With that, I'd like to hand it over to our Chief Executive Officer, Jim Mullen. Jim, please go ahead. Thank you, Ron, and good morning, everyone. Thank you all for joining us. I'm thrilled to be speaking to everyone today for Editas Medicine's review of the clinical data from our ongoing BRILLIANCE trial. For those of you who do not know me, I'm Jim Mullen, Chairman and CEO of Editas Medicine. I'm joined today by our company's Chief Medical Officer, Dr. Lisa Michaels, our Chief Scientific Officer, Dr. Mark Shearman, and the Senior Principal Investigator of the BRILLIANCE clinical trial, Dr. Eric Pierce. During the next hour, we plan on reviewing our EDIT-101 program and initial findings from this trial. Today marks one of hopefully many more important milestones in Editas's journey. Early today, one of the principal investigators of the BRILLIANCE trial presented initial clinical trial data at the International Symposium on Retinal Degeneration. These initial results demonstrate a tremendous step forward for patients with Leber congenital amaurosis type 10, and a glimpse into what we believe is possible for many other inherited diseases. The foundational science behind CRISPR-based gene editing is changing how medicines are developed, and applications using this technology are steadily creating scientific and medical breakthroughs. Editas continues to be at the forefront of these next generation medicines, and today's results demonstrates an important achievement for patients and the broader medical and scientific communities. Specifically, early results from our dose-finding safety trial show evidence of gene editing, resulting in clinical improvement and an absence of serious safety concerns. We believe these findings validate the fundamental notion that we can safely deliver a clinically effective gene editing medicine directly to patients in order to treat their ocular disease, an important advance that helps de-risk our subsequent ophthalmology programs. Before I turn it over to Lisa, I want to acknowledge and thank the patients enrolled in this trial, as well as the participating practitioners who witnessed firsthand how this technology can improve the patients' quality of lives. This progress would not have been possible without your involvement and support. Editas's mission has always been to discover and develop a novel class of genome editing therapeutics, and today's event brings us one major step closer to achieving that goal. With that, I'd like to hand it over to Lisa Michaels. Thank you, Jim, and thank you everyone for joining us this morning. As Jim mentioned, today marks an important landmark for the company. Editas Medicine was the first company to ever administer an in vivo gene editing medicine to humans, so it's exciting to be able to share the company's first clinical data from the phase I/II BRILLIANCE study. The ongoing trial is currently evaluating the safety of EDIT-101, as well as potential clinical benefit in the treatment of blindness due to CEP290 retinal degeneration, which is also known as Leber congenital amaurosis type 10, or LCA10. CEP290-associated retinal degeneration is a rare inherited disorder affecting about three out of every 100,000 children worldwide. It's autosomal recessive, which means that to be affected, the person has to inherit two copies of the defective gene, one from each parent. If you can repair at least one of these copies, you can potentially reverse the disease. Despite being rare, it is the most common cause of early onset inherited retinal degeneration. The loss of vision is caused by early loss of photoreceptors in the eye. However, even into late adulthood, there remains a small area of normal anatomy in the central part of the retina, and this provides the opportunity for gene correction. Now, diagnosis is usually made in the first years of life, as severe vision loss occurs in early childhood, and the loss of vision is multifold. In addition to loss of visual acuity, the type of vision measured by reading the letters or shapes on an eye chart, there is also a loss of peripheral vision and night blindness, which is an inability to see in dim light. Even people with some visual acuity see the world through this narrow aperture and only in bright light. Even then, the world can be fuzzy. Because the vision loss occurs early in life, most individuals have nystagmus, uncontrollable eye movements that make it difficult to fix on an object. Some affected individuals are fully blind or can only discern light from dark. Now, the health consequences of blindness go beyond just vision and may impact mobility. Individuals are at much greater risk for falls and injury, and people with vision loss due to mutations in the CEP290 gene cannot drive, and then you're not able to independently use public transportation. Further, there is real and typically adverse impact on social function social school performance, and employability. A treatment that can stop further vision loss, or even better, correct permanently and permanently reverse the vision loss, is greatly needed. Small improvements, such as being able to see obstacles better and see the face of a family member or even get around in the dark, can have a real positive impact on a person's life. Blindness can result from a mutation in the CEP290 gene. Loss of vision results from disrupted production of the CEP290 protein, resulting in a protein deficiency. In the eye, the CEP290 protein plays a very important role in the ability of photoreceptors to convert light into signals that the brain translates into sight. The CEP290 gene is too big to be delivered by established methods of gene delivery, including the adeno-associated virus vector or AAV. This means it cannot be treated with a similar approach as a gene therapy drug, LUXTURNA, which is approved for the treatment of retinal degeneration due to mutations in the RPE65 gene. However, the gene editing apparatus that can surgically remove the mutation from CEP290 does fit in an AAV vector, so it's an ideal application for the use of gene editing. EDIT-101 codes for two guide RNAs that specifically frame the targeted IVS26 mutation and permanently remove it. In non-clinical work, we have demonstrated that by cutting out the mutation in CEP290, it's possible to restore gene function and restore normal production of the protein. If one specifically delivers the gene editing apparatus to the photoreceptors in the central retina and corrects the mutated CEP290 gene in those cells, it should be possible to restore photoreceptor function, improve retinal sensitivity to light, and hopefully improve functional vision. CRISPR-Cas9 gene editing for the CEP290-associated retinal degeneration is a highly innovative method, preclinical data supports the high specificity and the fidelity of the approach. EDIT-101 was designed to target the specific part of the retina where the viable photoreceptors remain and limiting potential interactions with other structures in the eye. It was also designed to be a one-time treatment, resulting in permanent correction and avoiding need for repeated or recurrent injections. To do this, EDIT-101 was developed using the AAV5 vector with high tropism to retinal receptors, and it's delivered locally to the specific part of the retina where the targeted cells live. For those interested in the detail of the science, the vector comprises of DNA encoding Cas9 expressed under photoreceptor specific GRK1 promoter, and also for two highly specific guide RNAs that ensure site-specific delivery to the mutation site. Our non-clinical data support the specificity of the approach and the lack of off-target effects. Before I hand off the presentation to Dr. Pierce, who will give you more detail based on his personal experience treating these patients, I'd like to share a little more background. When Editas embarked on the BRILLIANCE trial, no one had previously attempted gene editing in the human body. It was not known how humans would react to the CRISPR-Cas enzymes when delivered to the eye using an AAV as a delivery system, and there was a lot of concern about the potential immune responses. For this reason, the study is primarily designed as a safety study. Today, we share the collected safety data on the first six subjects treated, two subjects in the sentinel low dose cohort, and four subjects who have been treated in the mid-dose group. The observations we have collected to date support the safety of using CRISPR-Cas9 in this clinical setting and for the treatment of human disease. Importantly, we have not observed any serious adverse events associated with the treatment, including observations for more than a year in the first two patients treated. Most encouraging is that we have not observed any dose-limiting inflammatory reactions, and most adverse events have been mild, with the majority related to the surgery required to perform the subretinal injection. The safety observed to date has allowed us to move to the next phase of the study, which includes treatment of adult patients at the highest planned dose and also the start of enrollment of children. Additionally, we present early top-line data on the subjects who, as of the August 4th cutoff date, had at least three months follow-up after treatment. Why is this? A question I've received frequently is when is the earliest time point we would expect to see a clinical benefit from editing? We know from the non-clinical data that it may take six weeks or even longer for the effects of editing to occur in the eye. Additionally, time is required for the treated eyes to heal following the subretinal injection surgery. Consequently, although the effects of editing might be observed earlier, we believe that the three-month time point is the first where we can collect consistent and reliable observations for comparison to both baseline and subsequent patient visits. This decision is supported by the data we share in which we were able to detect measurable changes in BCVA or FST by this time point. More importantly, for some of the patients, we have evidence that these changes are sustained on more than one measurement. At the time of the data cutoff, the fourth patient in the adult mid-dose cohort did not yet have the three-month follow-up visit. An unanswered question is whether three months after treatment is only the earliest time point in which a change in function can be measured. It is possible that benefits may continue to accumulate over time as the photoreceptor function improves. To answer this question, we continue to follow these subjects prospectively, and for now continue to collect clinical measures to observe for additional changes over time. Finally, one of the challenges of the study is how do we identify efficacy, which depends on using measurements of vision rather than a simple assay such a blood test, which would let us know if we have corrected the CEP290 protein's efficiency. Because EDIT-101 is being used to treat the small and important macular region of the retina, there's no easy test or ability to biopsy the eye to confirm that effective editing has occurred. Consequently, an important secondary outcome of the BRILLIANCE study is the collection of multiple exploratory endpoints that can be used in the clinic to capture changes in retinal function, as well as functional vision. Many of these are difficult to collect in people with restricted vision or with an inability to fix their gaze on an object. There is also a lot of inter- and intra-patient variability in some of these measures. Concurrent to the BRILLIANCE study, Editas is also collecting prospective natural history data that explores which measures are reproducible on repeated measurements, and thus best in capturing the effects of editing in the eye in this patient population. From this unpublished data, the FST appears to be a sensitive measure of retinal function, and we have also observed that individuals with CEP290 retinal degeneration have consistent measurements for BCVA, and their performance on our version of the visual function navigation maze doesn't meaningfully change when repeated over multiple measurements over a year. Pupillometry is also reproducible, but it may not be a sensitive measure of potential editing effect. For today's summary, we have focused primarily on FST, BCVA, and the VNC, the navigation maze, as they show the best consistency on repeated measurements. To summarize, no DLTs or serious adverse events have been reported in our ongoing BRILLIANCE study. Most excitingly, we do see early signs that indicating that productive edits have occurred and potential signs of clinical benefits for the patients treated. As safety has been supported, we are now taking the study to the next step and treating patients in the next planned higher dose. Our preclinical data supports an expected dose response, we're hopeful that more edits resulting from administration of higher doses will translate into a stronger clinical effect. Additionally, safety has also supported moving into younger patients in whom we believe that there is the strongest potential for benefit, and we are starting enrollment in the first of two planned pediatric cohorts. Finally, this first gene editing trial in humans reflects the results of years of hard work, and I'm very proud of the progress that Editas has made in advancing our programs into clinical development. The results shared today support our ongoing clinical development efforts, and I'm very grateful to the scientists and the clinicians and our collaborating institutions who've made this possible, especially to the patients and their families who have participated in the research. I think that's an apt transition over to Eric, who has been a longstanding partner with Editas. Dr. Eric Pierce is the William F. Chatlos Professor of Ophthalmology at Harvard University, with clinical appointments both at the Harvard Medical School and the Mass Eye and Ear. He's well known for his clinical and research contributions to ocular genomics and retinal diseases. Not only has he increased the public's awareness of inherited retinal diseases such as LCA10, but he's also helped potential patient participation in other gene editing and gene therapy trials, which undoubtedly helps bringing CRISPR- mediated medications closer to patients. We're very lucky to have Eric as the Senior PI in the BRILLIANCE trial. His history with the study goes back way farther than mine, and his enthusiasm and support for the technology and the program has been incredible. Eric, I want to thank you for being a great partner in this trial. Please go ahead. Thank you very much, Lisa, and thanks to you and your colleagues at Editas for inviting me to speak in this webinar. As we indicated, I've been enthusiastic about CRISPR- mediated gene editing since it was initially reported, and that's one of the reasons why Mass Eye and Ear is delighted to partner with Editas on the clinical studies of CEP290 associated treatments for CEP290 associated retinal degeneration. In addition, the discovery work, as you've indicated, on therapies for other genetic forms of inherited retinal degeneration. As you can imagine, the opportunity to help develop sight preserving or restoring therapy for patients with CEP290 associated retinal degeneration is really exciting and rewarding. If we could move on to the next slide, I'm going to talk about the trial design and some of the results that we've been observing, as Lisa described. The design of the BRILLIANCE trial is a standard dose escalation study with three cohorts of treatment for adults at low, medium, and high doses as indicated. As Lisa described, the adult subjects in cohorts one and two have been treated, and the first subject in cohort three at the high dose in adults has also been treated. Based on the safety data, which we'll describe, the independent data safety monitoring committee has approved enrollment of subjects in the first pediatric cohort. All subjects in the study are monitored closely following the surgical treatment to deliver the gene editing therapy, and then followed every three months in the first year, and then less frequently thereafter for two more years to fully assess safety and efficacy. Next slide, please. In order to participate in the study, the subjects have to meet key inclusion criteria. For adults, obviously, this is to be 18 or older. For cohorts 1 and 3, for pediatric subjects, they need to be between ages three and 17, and they all need to have a clear genetic diagnosis of CEP290-associated retinal degeneration and be at least heterozygous for the intron 26 mutation, which is the target of the therapy, as Lisa described. The subjects in cohort 1, the sentinel cohort treated with low dose, had impaired vision in the light perception or black light discrimination level. The sentinel subjects in cohorts 2 to 5 also need to have more impaired vision in the range of light perception to about 20/800 on the Snellen chart or logMAR of 1.6. The following subjects in cohorts 2 to 5 can have better vision up to 20/50 Snellen equivalent. Subjects will be excluded from the study if they don't have a clear genetic diagnosis of CEP290-associated retinal degeneration, as you can imagine, if they're able to pass the Visual Navigation Challenge Course at the most difficult level, and I'll describe that in more detail shortly, if they had recent surgery or infection, inflammation in their eyes, if they have a history of steroid-induced glaucoma or increased pressure inside their eyes, if they aren't willing to take oral prednisone, or if they've had and participated in other studies of other therapeutic modalities such as other gene therapies or oligonucleotides. To move on to the safety data in the next slide. Sorry, this is baseline characteristics of subjects on the next slide. As you can see, this slide describes the baseline characteristics of the first six subjects treated in the trial. Ages range from 9 to 63. The subjects in cohort 1 had more impaired vision, as indicated. Sentinel subjects in cohort 2 also had relatively impaired vision, but visual function and acuity as the subjects enrolled later has been better as planned. All the subjects are at least heterozygous for the intron 26 mutation of CEP290. The sentinel subject in cohort 2 is homozygous for this mutation. Now, if we can move on to the next slide for the safety data. In order to assess safety in the BRILLIANCE study, we're evaluating presence of dose-limiting toxicities and adverse events related to both the editing therapy and also the surgery required to deliver it. The graphic here depicts how dose-limiting toxicity is defined, that is decreased vision of at least 0.6 logMAR units that was sustained, or loss of light perception in patients with more poor vision that was sustained, or corticosteroid-unresponsive inflammation in response to the therapy, or severe non-ocular adverse events. A summary of the safety data to date is shown on the next slide. As Lisa described, we're thrilled there have been no dose-limiting toxicities or serious adverse events for the subjects in the first two cohorts. There have been, to date, no treatment-related cataracts, edema, or retinal thinning observed. As indicated in the table below, the majority of the adverse events identified have been mild, most have been related to the surgical procedure to do the subretinal injections to deliver the gene-editing drug. For example, eye pain was the most common reported, and this resolves as it typically does following the surgical procedure. Only mild treatment-related inflammation has been reported, and it's all been responsive to therapy. No Cas9 specific antibodies have been detected, and all of the adverse events listed in the table have resolved at this point. Based on those data, the IDMC now has supported enrollment of pediatric subjects into the mid-dose cohort, which has begun, as Lisa indicated. Moving on to the next slide. I'm now going to focus on the data we've observed related to efficacy in this study. As Lisa described, this is focused on using three primary measurements of vision that were observed to be the most reliable and consistent in the natural history study of CEP290-associated retinal degeneration that's in progress. This includes visual acuity, full-field light sensitivity thresholds, and the Visual Navigation Challenge, and I'm going to describe all three of these in a little more detail so you can understand how efficacy is being assessed. For example, visual acuity on the next slide. Subjects who can read have a standard test using letters on an eye chart. This is the standard Early Treatment Diabetic Retinopathy Study, or ETDRS, chart, which provides logMAR acuity from reading smaller and smaller sized letters. For pediatric subjects who aren't able to read letters, it's the same kind of chart using pictographs, and for subjects with more impaired vision, we're using the Berkeley Rudimentary Vision Test, which measures vision using other kinds of stimuli, such as the grating acuities shown here. In the next slide, we can get a brief description of the full field light sensitivity threshold test, or FST. This is a measure of how sensitive someone is to light, how good their retina is at detecting the levels of light. In order to perform the test, subject looks into a dome, as shown on the slide, and light stimuli are presented. In order to do this test, there's a sound tone emitted by the dome, and then the light is presented. If the subject can detect the light, they press the green button. If they can't, they press the red button, and in this way, we can measure the threshold at which the lowest level of light that is needed for them to perceive it or their sensitivity threshold. We use red, white, and blue lights in order to distinguish between rod and cone responses. The navigation course is shown on the next slide. This is a multi-luminance mobility test, which in some ways is similar to the kind of course we've seen in the results from the RPE65 gene therapy studies sponsored by Spark, which led to the approval of the drug, which is now called LUXTURNA. In this navigation course, there are four types of courses. The most difficult one is a low contrast course, chooses a low contrast path for subjects to follow, has multiple objects, and is performed at eight different levels of illumination. If a subject can pass this test at the most difficult, lowest level of illumination, which is 0.3 lux, or like walking outside on a partially moonlit night, they get a score of 21. Many of the subjects in our study can't perform that test at all. There are additional navigation courses to address different visual function. The high contrast course uses the same kind of path as the low contrast one, but is performed with higher contrast paths, as you can see on the slide, also with multiple obstacles and also at eight levels of light, and subjects can get a score of 16-13, depending upon which level of light they pass the test at. Subjects who are unable to perform that also can use the high contrast room exit course. This is a simpler test with a straight path leading, for example, to a room exit. The high contrast test has high contrast paths, high contrast obstacles, and is performed at three levels of illumination, finding scores of 3-5. The easiest course is the backlit room exit course, where the path is illuminated as shown, and the obstacles are illuminated. This is performed at two levels of light, giving us scores of 1- 2. You can imagine a subject in, for example, the sentinel subject in any of the cohorts might be able only to do the backlit room exit course. What we're hoping to observe is if their vision improves, they might be able to perform courses more difficult or perform the same course at a lower level of illumination, as we'll describe. Next slide, please. To get to the subject data, this is the data for the sentinel subject in cohort 1. For all the five data slides related for subjects, the data is presented so that if we're showing change in baseline, an improvement is shown by downward deflection of the curves over time. It's a little counterintuitive. For example, this subject appeared to have an improvement, a downward deflection of the vision for their treated eye at six months. Unfortunately, due to the COVID pandemic, they haven't been able to return to the treatment center for further evaluation. We're really looking forward to seeing if this improvement is sustained at further follow-ups. This subject did not have consistent improvement in their sensitivity to light or in their ability to do the navigation course. Next slide, please. For the second subject in cohort 1, this subject also had poor vision starting at light perception. It appeared they might have had improvement, again, a downward deflection in their acuity at three months. This was not sustained at follow-up visits. They appear to have improvement in their ability to do the navigation course, again, with a downward deflection of the curve, although this was observed with both eyes, so we're uncertain if it's a treatment effect. I will say this subject very clearly describes, subjectively, improvements in their vision. For example, they now describe that they can see where food is on their plate, which they couldn't do before, and they're starting to be able to perceive colors. We're looking forward to further follow-up for this subject. For subject 1 in cohort 2, we're very excited to share these data. This subject started with impaired vision in the count fingers/hand motions range, and at 1.5 months following treatment, demonstrated a significant improvement in acuity of 0.6 logMAR units, as shown with the downward deflection of the acuity graph of BCVA. They've also demonstrated consistent increased sensitivity to different levels of light, as shown in the FST graph, and improved performance on the Visual Navigation Challenge Course in the treated eye, showing improvement, again, in the downward direction. We're excited about these data if they show sustained improvement. Why don't we show you what the changes in the Visual Navigation Course look like on the next slide. As you can see on the baseline video here, this is the subject performing the high contrast course at the highest level of light, 500 lux, which is like being in a very bright lit room. As you're about to see here, they fail on this test because they step outside the course right there. In contrast, in the month six follow-up visit, they're performing the same course, but at a much lower level of light, like walking in a dim corridor, and they're able to follow the course effectively and avoid the obstacles, and they don't step out of the pathway. This is a clear improvement, and the subject describes these improvements in their vision. They say they can see lines better, they can find objects they drop on the floor, and they can navigate better at work, for example, by detecting doorways more easily. We're very excited about these results. Let's go on to the next subject, please. Next slide. Subject 2 in cohort 2 started out with vision in about the 20/500 range. They have experienced consistent improvement in their ability to detect lower levels of light, as shown in the middle graph for FST. This would be consistent with seeing better when it's dimmer or darker. They've also had a little improvement in their navigation performance, although to date, no measurable change in visual acuity. We're looking forward to continued follow-up and hope that the changes in FST results presage additional improvements in vision. Subject 3 on the next slide had the best vision so far enrolled in the study at about 20/80 to start with. As you can see, they have not shown consistent improvement in any of these three measurements at the three-month time point, although at a recent follow-up visit, the subject did describe that they feel subjectively the vision in their treated eye is now clearer than it used to be. Again, we're looking forward to further follow-up for this and other subjects going forward. Next slide, please. In summary, we're very excited that early analyses in the mid-dose cohort show signs of efficacy. We think this is a very important result. As Lisa described, it's our way of telling if editing of the CEP290 gene is occurring in these subjects' retinas, in their light sensitive cells, which is then restoring light sensitive cell function, which underlies their improvements in the metrics we've described. We're thrilled to look forward to continuing this study, and really excited about the possibility of developing an effective treatment alternative for patients with CEP290-associated retinal degeneration. Really, I think, as Lisa described, these first in human data demonstrate the potential of biological effect of gene editing, which to me supports further development of gene editing therapies for other forms of inherited retinal degeneration, and potentially other inherited diseases going forward as well. Thank you very much. Lisa, back to you. Well, thank you, Eric, thank you for helping to explain the trial and the clinical findings. I really appreciate some of the insights of the conversations that you had with the patients regarding their subjective feelings that they have had some benefit from the treatment. Well, we believe here at Editas that the findings discussed today do provide initial proof of concept for our ocular portfolio, as well as our broader in vivo gene editing platform. These results reinforce our confidence in advancing our other ocular programs, such as those for Usher syndrome and autosomal dominant retinitis pigmentosa, which impact even larger patient populations than the CEP290 related diseases. We're excited to continue the trial and enroll additional patients, and I look forward to sharing additional progress to you on this program next year. With that, I'll hand it back to Jim. Thank you, Lisa, and thank you, Eric, for joining us today. As Lisa mentioned, we believe these early data validate our in vivo's platform proof of concept. As we think about our long-term strategy, today's findings help strengthen our foundational technology and provide us with the clinical evidence to progress our pipeline. There are hundreds of conditions that could potentially be addressed with this technology, and we are actively exploring a number of them in our preclinical and discovery work. Again, we want to acknowledge all current and future patients of this study. We understand the commitment this means for you and your families, and we owe you a great deal of gratitude. Thank you once again to Dr. Eric Pierce and the rest of the principal investigators for partnering with Editas. For everyone joining us on today's webinar, we thank you all for your interest and support. With that, we're happy to answer questions with the time we have remaining. Thank you, Jim. We will now move to the Q&A part of our webinar. If you want to ask a question, please use the raise your hand button, if you have it available. If you do not have the raise your hand button option available, please use the ask your question option available on the right-hand side panel to submit a written question. The first question comes from Joon Lee. Please unmute yourself and ask your question. Hi. Thanks for taking the question. Can you guys hear me? Great. With the data that you have to date, what do you envision could be an approvable endpoint for a pivotal trial? Is that still BCVA or something more innovative? The second part of the question is, given the better efficacy in the homozygous that you're getting at the interim data, do you think getting it approved first in homozygous only and then potentially expanding that into heterozygotes could be a strategy that you may consider? The last part of the question is, if it is BCVA that you ultimately need to pursue for approval, what do you think is the hurdle, the clinically meaningful hurdle for that? Thank you. All right, Joon, that's an awful lot of questions in one fell swoop. I'm going to start with the first one. That is why I think of approvable endpoints. At the moment, the clinical data is at least suggesting. Again, it's a very small number of patients. We haven't even established the dose that we will be moving forward with. The first thing I want to emphasize is that the non-clinical data does support that we should see improvement with moving up to the next dose cohort. That data would suggest that we would be achieving editing efficiency somewhere around 50%, which as long as we continue to not see any safety concerns, that's really our next obvious step for evaluating effectiveness. So far, the data, at least in a very small number of patients, does suggest that we can see meaningful changes in BCVA or in functional navigation. We know those are both approvable endpoints. We also know the potential of being able to use FST in combination with that to support meaningful changes in the patient. It's a little premature for me to identify specific endpoints, but if Eric wants to jump into that, I certainly welcome him. The second part of that question, I think, is where do we actually see the meaningful benefits? Lisa, I think you're correct with your assessment in terms of potential approval endpoints. To address the question about what's a significant level of improvement, 0.3 logMAR improvement is considered clinically significant. We're definitely achieving that range. I think that's only really on one patient so far. As we move forward, we're hopeful that we'll be able to see a range of improvements across multiple different patients as they move in. The second one is resolving to the homozygous. We've only had one patient so far enrolled who's homozygous. Okay. Again, it's a very small number of patients. I think at this point in time, I'm not writing off homozygous versus heterozygous. The way this works is this is an autosomal recessive disorder, and as a consequence, we only need to repair one allele in the cell. It really shouldn't make a difference if the patient's homozygous or heterozygous. We've only had one homozygous patient in the study. She's actually one of the patients with the worst-seeing eyes. We have the opportunity, moving forward, to evaluate a wider range of patients, and that will be considered as part of the development program. Thank you. We will now take a question from Philip Nadeau. Please unmute yourself and ask your question. Good morning. Thanks for taking our questions. Two from us. First, on the efficacy, we were a bit surprised that the older patient had benefit, while the younger ones, at least thus far, didn't seem like they did. Curious to hear your potential explanations for why that is the case, and does it at all make you question whether the 20/50 Snellen criteria that you've instituted for patients beyond the first patient age cohort is reasonable? It does seem like maybe efficacy is inversely correlated to the initial BCVA that the patients have. The second question on inflammation. Can you give a little bit more information on the duration of the inflammation, and whether you think it's due to the capsule or the procedure itself? Thank you. Eric, I'm happy to let you jump in on that because you're the one who's had the hands-on experience on both of those. Yeah. Sure. With regard to inflammation, to take the second part of your question to start with, most inflammation that we've observed has been pretty mild and quite steroid responsive. It's certainly within the range of what would be expected following an intraocular surgical procedure. In terms of the relationship between acuity or age and potential response, I just don't think we have enough patients yet to know for sure. There is a challenge with treating subjects with better vision with subretinal injections in that they have to recover from surgery before we can observe potential improvements. I think in the two subjects with better acuity, who are the third and fourth subjects in cohort 2, we're really just getting to the point in postoperative care and follow-up that we can begin to tell if they have a response to the therapy or not. I think we need more data to know which subjects are going to be potential responders and which might be best suited for treatment with this modality. Eric, I have to admit, I'm quite impressed that the worst-seeing eye in that cohort has so far to date shown the best benefit. I think my other question is in patients who have at least some better visual acuity, are we looking for more subtle changes related to improvement in vision and how we would actually capture those? I think the improvement observed in the first subject in cohort 2 reflects this issue of structure function differentiation that's come up as you described in your comments in the webinar. I think the improvement that patients experienced reflects their intact structure, observable on ocular imaging studies, and correction of the genetic defect in the observable cells, which then restores their structure and function. To me, that's a very optimistic finding. It implies that for any subject with intact retinal structure, meaning intact outer retinal cells, photoreceptor cells observable by imaging techniques, that there's the potential for improvement. I think we're just going to have to have more experience with subjects across the different severity spectrum of disease to know how much improvement could be expected, for example, in someone starting with better vision. I don't know whether they're going to have improvement in acuity or whether their improvement might be more subtle, as you suggest, perhaps with FST responses or navigating the Visual Navigation Challenge at lower levels of illumination. I think the early findings suggest all of that's possible, and we're just going to have to see what we learn from further study. That validates us continuing to follow them with both FST and the visual navigation aids as we move forward prospectively. I think the other part of the question I want to come back to is, there's a lot of concern about inflammation in the treatment and whether or not that's dose-limiting or might potentially is clinically relevant. Are there any concerns that you've had in your hands related to inflammation? I don't know. What are you seeing? Is it beyond just what you normally would expect with this type of surgical procedure? We're really pleased with the lack of inflammation that we're observing in the treated subjects. For example, as was mentioned, the first subject in the adult high-dose cohort has been enrolled. They're early in their follow-up, but even at the higher dose, we have not observed significant inflammation in the first six weeks post-treatment. I think it's a very promising sign. All right. I stole the questions for a bit. I'll hand it back. Thank you. We will now take a question from Liisa Bayko. Please unmute yourself and ask your question. Okay. I think I'm unmuted. Thanks for answering the question about the patients with better eyesight. I was a little curious about that, Lisa. That was my first question, which we can check the box on. My second question. In some patients, we've seen a change in BCVA, in some we've seen FST, in some maze. Would you expect some sort of correlation of these things or to see improvement on multiple metrics? Why do you seem to see some sort of within these different parameters, changes on one but not the other, and it kind of varies from patient to patient? I was curious about that. Well, I think the first thing I'll interject is that the maze is actually sort of measuring two different things. We are evaluating the ability of patients to function in increasingly complex mazes and obstacles at different levels of light. We know in most of these patients that they have significant impairment of being able to see in low light. Those who have the better vision do much better at higher light. Every one of these configurations of the maze basically follows, can you do the maze at high light? Can you do it at dim light? The other one is also the complexity of the path that the patients have to follow, which would actually require them to be able to see those obstacles. I think we're measuring two different things in our current version of the maze, and we are seeing changes in both of those, both the ability to maneuver much more complex mazes as well as at different levels of light. Okay. As it pertains to BCVA, I know there's different ways to measure it, right? You discussed on one of your earlier slides, there was the kind of standard eye chart in a way, and then there's the chart with the lines. Were all the patients using the same chart, or if I'm understanding correctly, patient 1 was using the chart with the lines and maybe the others weren't? I guess is the threshold the same of -0.3 logMAR as being a clinical and meaningful change across all of those different methods? Thanks. Sure. The clinical protocol includes the use of the Berkeley Rudimentary Vision Test, which is the one you're referring to with the grating acuities, the lines that were faced in different directions, for subjects who can't do the ETDRS chart. The ETDRS chart is a well-used and understood tool in vision science. We know that a threshold, for example, of a change of 0.2 logMAR units for people who can read those letters is reliable. It's not noise, we know the FDA requires a three-line change as an approvable endpoint. There's less experience with the Berkeley Rudimentary Vision Test, which is designed to detect or discriminate different levels of low vision. That I think we would have to figure about what would be an approvable endpoint from that test. It works very well at distinguishing between someone who, for example, might be able to see hand motions. That's the clinical description we would give if we were just examining them without that tool. Now we can break it down and see, well, what size grating did they detect, and assign a logMAR score to it. It gives us a chance to quantify vision at the low end of the spectrum, which I think is very useful. Eric, I think one of the questions that I think will come up is how meaningful is 0.3? I think the other one is understanding that ProQR and sepofarsen has actually reported 0.7 in, quite frankly, a different patient population than we're exploring here. Do we need to read that threshold, or is 0.3 and better actually a really good achievement? 0.3 and better is a really good achievement. That's an approval endpoint. That's fantastic. You can validate that by hearing the patient's reports, that the patient-reported outcomes are consistent with improved function and quality of life, and they have those kinds of improvements on the ETDRS chart. Thank you. We will now take a question from Luca Issi. Please unmute yourself and ask your question. Oh, great. Can you guys hear me okay? Yes, sir. Terrific. I have a few questions, but they're all pretty quick. The first one is a neutralizing antibody. I know you mentioned no neutralizing antibody to Cas9. I'm wondering if you've seen any neutralizing antibody to the actual vector. Again, just asking that in the context of potential redosing. Two, clarifying questions in the DLT. How long was the DLT assessment period? Was it just four weeks post-surgery, or was it throughout the follow-up of the patients? Three, maybe on sickle cell disease, Lis, I think it looks from the 8-K that the dosing of the first patients was postponed from the second half of 2021 to the first half of 2022. Wondering if you can elaborate on that. Thanks so much. Okay. Let's just dispense with the last one really quickly. We actually are moving forward very quickly with the clinical trial in terms of patient enrollment, patient selection, and screening. We actually have a number of patients that are currently undergoing electrophoresis processes and having their cells. I think even today we have [four incoming cells] being delivered to our site. At the moment, each one of these patients is requiring more than one pheresis event, and then the cells are being edited. We're getting ourselves into the holiday period. We're just kind of looking at the crunch of timing at the moment as related to the events that have to take place in order to get the patients pheresed, as well as the timing of the holidays and being able to dose the first patient. We would have liked to have gotten in at the end of the day, but I wasn't going to have a patient enter the hospital for probably a six-week hospitalization on Christmas Eve. As for the other two questions, I guess real quickly, neutralizing antibody, not all of the patients have had antibody responses, and the titers are very low. They may not even be clinically relevant. At this point in time, there's nothing to suggest that we cannot dose the second eye. Mark, you're welcome to jump in if you want to add any more to that one. No, I would agree. The levels are low, and actually there are preclinical data suggesting that those neutralizing antibodies are not going to interfere with dosing the second eye, and in fact, re-dosing of the same eye could be possible too. That would, we're predicting, would not be necessary based on the mechanism of action. I guess the last question is related to the DLT. Quite frankly, as part of a safety trial, DLT can happen at any point of the clinical trial, but the primary evaluation period for safety related to the procedure and the injection is actually in the first 28 days. Thank you. We will now hear from Joel Beatty. Please unmute yourself and ask your question. Hi. Thanks for taking the questions. The first one is, how confident are you that the currently planned high dose of 3 x 10^12 will be the highest dose that you'll need to test in this trial? The second question is, some of the patients had transient improvement on certain measures in their contralateral eye in the data presented today. Any way that that could be due to drug or is that just some random noise? I think I was writing down one of the questions, the second one. The transient one is random noise. I'll let Eric answer that one. Sure. Subjects with CEP290-associated retinal degeneration have nystagmus, which means their eyes bobble back and forth, often due to poor vision in childhood. What we observe is that improvement in vision in one eye can reduce the degree of nystagmus, which can, in some cases, confer improvements in vision in the second eye. I think there could be a little noise in some of the metrics. We're still collecting data. As we've been saying, this is early in the study, but some improvement in function with the non-treated eye would not surprise me if the nystagmus is reduced following improvement in vision in the treated eye. Fixing of gaze is one of the clinical endpoints that we're collecting, so we'll have an opportunity to be able to evaluate that moving forward. Thank you. Yeah. I think I missed the first part of the question, though. The first part of the question was about the potential dose that might be used in this study. Was the current high dose definitively the highest dose that will be used? No, thank you, Eric. At the moment, we're pretty much extrapolating dosing based upon the non-clinical studies that were collected. It appears that if we really want to try to get to that threshold of at least 40%, 50% or higher editing, that higher dose is the sweet spot. Whether that's the final dose will be largely predicated on safety and what we see from clinical findings. Thank you. We will now take a question from Gena Wang. Please unmute yourself and ask your question. Okay. Can you hear me now? Great. Thank you. I have two sets of questions. The first one. Hey, Gena, we can't hear you very clearly. Okay. Can you hear me now? Very softly. Can you hear me now? There you are. Perfect. Sorry about technical difficulties. Yeah. I have two sets of questions. The first one is regarding the measurement, I think more the BCVA logMAR. I think some already touched upon, wanted to ask a little bit specifically. When we look at the cohort 1, subject 2, the patient dropped. If we're only focusing on the study eye, the patient dropped by 0.9, which Dr. Pierce used at 0.3 will be very meaningful. The next visit come back all the way to the baseline. We saw also similar cohort 2, subject 2 drop by 0.2 roughly, come back to baseline. Just wondering how much measurement error in general for logMAR, and how much is the intrapatient variability, and that normally will be seen? That's the first question, similar question for FST and the navigation. We saw also some kind of bouncing back there. My second question is related to the inflammation. I know we discussed a little bit, do wanted to ask again. I think all these patients, if I understand correctly, they were already on prophy oral prednisone for six weeks. At what point was the onset of the inflammation, and how long does it last, and how was that resolved? Regarding those patients have inflammation, what are their status of AAV antibody? I think starting with the inflammation one, first of all, we're not seeing a dose-related response in inflammation. Most of the events of inflammation actually were reported in only one patient, and it was the first patient in the study. That's also the patient where we did have some truncated efficacy follow-up and data on her because of the problems related to COVID. All patients, in a relatively conservative fashion, were put on prophylactic prednisone at the beginning of treatment, which they received for about a month and then a taper. What I will share with you is that there was no need for additional therapy in most of those patients. The only one who received additional treatment, again, was that very first patient in the very first cohort. That dose effect has not been seen. It is not dose-limiting, it does not persist beyond the period of time that we would expect it based upon both the surgical procedure as well as have not required any patients require further duration of treatment as part of the study. Eric, would you agree to that? Yes, absolutely. Yeah. I guess the other one is still that question about noise in the data. I will throw in at least that our unpublished data so far from the natural history study, what we chose to share this time is the data that seems to be the most reproducible on follow-up on repeated measurements. At least in our hands to date, the BCVA is relatively stable, as well as the Ora-VNC maze. That still is yet to be further evaluated. I guess in terms of just some of the normal clinical variation that takes place, I'd ask Eric to just let us know what that tends to be in the clinic. As I mentioned, there's a lot of good data over many, many years regarding the reliability and test-retest reliability for accuracy of the ETDRS chart. There's less information available about the reproducibility of measurements taken with the Berkeley Rudimentary Vision Test. As Lisa said, in the Natural History Study, most patients are pretty steady in the measurements we get from the Berkeley Rudimentary Vision Test experience. We do see, from time to time, changes in patient acuity as measured with the BRVT, even not associated with treatment, just within the natural history study. The subject 2 in cohort 1 had, as we said, a 0.9 change in logMAR acuity as measured with the Berkeley Rudimentary Vision Test, but it was not sustained at subsequent visits. I think we'd have to ascribe that to some noise. Patients with inherited retinal diseases will tell you that they have good vision days and bad vision days. Perhaps that was a good vision day, and we'd love to see that recur, but I think we all have to be watching for consistent changes that are reproducible over time in order to ascribe them to a treatment effect. I think my usual example has always been what your eyesight is like at the beginning of a long Zoom day and what it is at the end of a long Zoom day. I think, again, this has always been one of the things that I've reiterated and emphasized over and over again, is we really want to see reproducible responses. We begin to see that not only are we starting to see reproducible responses in at least one or two patients, but we're also beginning to see consistent changes in more than one patient. For me, that's a very valid signal that we're starting to see effective editing. Thank you. As we are coming up to an hour, we have only time for one more question. The next question comes from Steve Seedhouse. Please unmute and proceed. Please keep in mind that we only have two minutes remaining. Well, thanks for taking my question. I'll be quick then. Can you comment if you had any positive anatomic improvement by OCT in any patients? Thank you. Eric's welcome to jump in, but I think that was actually answered beautifully at the seminar earlier today by Mark Pennesi. One of the challenges with imaging these patients is that nystagmus and the ability to get very good imaging on the back of the eye. It's a very important endpoint for us for safety because we're not seeing degeneration or changes in the back of the retina that would suggest that we're actually hurting the anatomy by treatment. The ability to be able to demonstrate, in a sensitive manner, restoration of the outer nuclear layer is still something I think we're evaluating, but is difficult to obtain at this time. Thank you. That was the last question, and this now concludes today's session. Thank you for joining the webinar, and we hope you have a great day. You may now disconnect.