Session 9: Advancing the Treatment of Retinal Diseases
Transcript of Part 1: Advancing the Treatment of Retinal Diseases
00:00:07;07 This is a project to develop a new technology for an ocular drug delivery device. 00:00:13;18 And since this is a collaboration between ophthalmology and bioengineering, 00:00:18;15 we'll have the presentation in two parts. 00:00:20;11 I'm Robert Bhisitkul. 00:00:21;16 I'm a retina surgeon at the University of California, San Francisco. 00:00:25;12 And I will introduce this with a clinical background, with a description of the diseases 00:00:30;16 that we're trying to treat, and with the unmet clinical need that we have currently 00:00:35;25 in the way that we treat patients with these retinal diseases. 00:00:38;15 And this will serve as an introduction for my colleague, Tejal Desai, 00:00:42;20 in Bioengineering at UCSF, 00:00:45;08 who will give a description of the translational research project that we have 00:00:49;22 and the progress that we've made with translating this technology to an ocular drug delivery device. 00:00:57;14 As background, I'll give... for some members of the audience that might not be ophthalmologists, 00:01:03;06 we'll give a brief description of the basic anatomy of the eye. 00:01:06;21 The eye of course is a small spherical structure. 00:01:09;10 The front part of the eye is to allow light to enter into the eye, to be focused 00:01:15;08 onto the retina. 00:01:16;10 And the retina is the neural tissue of the eye that's sensitive to light that sends 00:01:20;02 an image back to the brain. 00:01:21;24 The retina is... can be thought of as the wallpaper that lines the inside of the eye. 00:01:27;11 And the space inside the vitreous cavity is filled with a clear gel. 00:01:34;13 And it's that space that we use to inject a lot of the drugs that I'll des... 00:01:39;03 that I'll describe later to treat retinal diseases. 00:01:42;01 Now, the center of the retina, the bull's eye of the retina, is known as the macula. 00:01:46;17 And that's what we see here, as you... as you look through the pupil, straight back 00:01:51;01 into the center of the retina. 00:01:52;25 And if this postage sty... postage stamp-sized area of the retina that is really responsible 00:01:58;16 for all of our high-resolution vision, the vision that we need for daily function. 00:02:03;06 There's even a small area with a depression that's shown alongside here, where it's only 00:02:07;25 200 microns in size. 00:02:09;09 That's the fovea, and that's really where we get our 20/20 vision, our high-resolution vision. 00:02:14;11 So, this is the part of the retina that we're trying to protect with these retinal diseases 00:02:17;24 that I'll describe next. 00:02:20;02 Some of these retinal diseases that we see every day in clinic, that are... that are... 00:02:24;24 that affect many patients in the United States are shown here. 00:02:28;18 The first is age-related macular degeneration, or AMD. 00:02:31;28 The "wet" form of this disease causes blood vessels to grow underneath the retina, 00:02:37;08 causes bleeding and leakage of fluid underneath the retina and into the retina, and can cause 00:02:41;09 a blind spot and severe vision loss. 00:02:43;15 It's the most common cause of severe vision loss in the elderly population. 00:02:48;02 And it's estimated to affect about 200,000 people every year in the United States alone. 00:02:53;08 Another large disease category here is diabetic retinopathy. 00:02:57;26 It's thought that this is a disease that affects the working-age population mostly. 00:03:02;08 And there's 25,000 new cases of blindness from diabetic retinopathy. 00:03:06;08 And there's millions of patients that remain at risk for this every year. 00:03:09;19 In this disease, the blood vessels are abnormal again. 00:03:12;22 They leak fluid. 00:03:14;00 They leak blood into the retina. 00:03:15;05 And they cause macular edema. 00:03:17;08 A third category of disease that's very common, that we're treating every day, 00:03:21;03 is retinal vein occlusion. 00:03:23;02 This happens most frequently in patients with high blood pressure or with cardiovascular disease. 00:03:27;26 And it's estimated it affects about over 10 million people globally. 00:03:30;15 And here you have a blocked circulation in the back of the eye, near that macula. 00:03:35;13 And this causes fluid and hemorrhage to build up in the... in the macula, again causing 00:03:39;15 macular edema. 00:03:42;24 In the past ten years or so, we've had expanding drugs that we can use to treat these diseases 00:03:47;10 very effectively. 00:03:48;13 And we have a range of diseases, not only the ones that I talked about there, 00:03:52;19 but many other diseases that we're now able to treat for the first time. 00:03:56;22 Because of drugs that we are injecting into the eye... this is a class of drugs against 00:04:02;01 vascular endothelial growth factor. 00:04:05;09 The first one that became available was Lucentis and there's also Avastin and Eylea in this class, 00:04:10;11 and some other drugs, all of which we're injecting into the eye to treat these diseases. 00:04:15;05 And every year in the United States alone we're doing millions of these treatments. 00:04:20;02 This is what the treatment looks like from the patient's perspective. 00:04:24;09 It's done in the office with local anesthesia that you can see is being injected here. 00:04:28;28 And the eye is held open with this lid speculum; washed off with a sterilizing solution -- iodine; 00:04:35;27 and then we can give the injection of the drug that we're using directly into the eye. 00:04:41;20 And you can see this is difficult for the patient. 00:04:44;02 The eye is irritated afterwards. 00:04:45;20 It's painful. 00:04:47;07 The eye can have some unsightly hemorrhage afterwards for a few days. 00:04:51;20 But at the same time it's a very effective solution. 00:04:53;13 We can take a tiny amount of the drug, we inject it into the eye right at the target tissue, 00:04:58;12 and it's sequestered somewhat in the eye so that it doesn't get into the bloodstream 00:05:03;01 and cause unwanted effects, systemic effects, but is contained within the eye. 00:05:10;04 Other drawbacks... when we give these treatments for these diseases, they are frequent injections 00:05:14;24 that we have to do. 00:05:15;24 It's not a one-time treat... once treat... one treatment and you're done, 00:05:19;13 but it looks like we have to treat these patients as often as monthly. 00:05:22;17 And for a disease like macular degeneration, it's on average seven to eight times a year. 00:05:26;28 And unfortunately it's not just for one or two years. 00:05:29;22 As we learn more about these treatments, we see that we have to maintain this 00:05:33;11 regimen of treatment for many years, perhaps lifelong. 00:05:35;25 There are some other drawbacks from this therapy as well. 00:05:39;27 There's risks with this injection. 00:05:41;20 You can get a low risk of a serious infection inside of the eye. 00:05:45;05 And then there's the treatment burden. 00:05:47;01 It's un... it's painful and uncomfortable for the patient, but also the patient 00:05:51;06 and their family have to come into the office for frequent, ongoing visits. 00:05:55;03 The doctors and their staff have to handle this workload. 00:05:59;02 And so it's a significant treatment burden that I think we've... we still have not completely 00:06:03;26 adapted to. 00:06:05;23 From the... from the pharmacologic standpoint, when we inject these drugs into the eye 00:06:10;03 we have peaks and troughs. 00:06:11;16 When we initially inject it into the eye as a bolus, we have an order of magnitude 00:06:15;22 too much drug that's in the eye that's not needed. 00:06:18;07 And then it rapidly begins to decline so that there's a subtherapeutic tail that occurs, 00:06:22;21 and there's not enough drug left in the eye at somewhere around a month. 00:06:26;09 So, those... these are all our motivations to try to find a new way to deliver drugs 00:06:31;00 into the eye besides just injecting them directly into the eye as fluids. 00:06:35;14 From here, we'll concentrate on one of the diseases that I talked about, 00:06:38;13 wet macular degeneration, wet AMD. 00:06:41;16 And this is for elderly patients. 00:06:43;05 And this is a depiction of what it's like from their standpoint. 00:06:45;26 The patients, once they have the onset of the disease, develop blurriness. 00:06:49;10 They develop a blind spot. 00:06:50;18 They develop distortion in the center of the vision, so that they can have severe vision loss. 00:06:55;25 About seven or eight years ago, we had a major breakthrough in treating macular degeneration 00:06:59;15 with a drug called Lucentis. 00:07:01;11 This is a biologic drug. 00:07:02;27 It's an antibody fragment against VEGF. 00:07:06;23 This is a... this graph is showing a Phase 3 clinical trial over two years. 00:07:11;26 And on the y-axis we're seeing the change in vision. 00:07:14;28 So, above... going up... going upward is an improvement in vision, going downward is 00:07:20;04 a decline in vision, over time. 00:07:22;16 And you can see from the blue line in the control group, this is what it used to 00:07:26;02 be like for our patients. 00:07:27;06 With the onset of wet macular degeneration, there was a steady, inevitable decline in vision 00:07:32;06 for almost all of the patients, so that they had severe vision loss over a year 00:07:37;10 or two years, to the point where they would almost universally become legally blind. 00:07:42;22 The red line shows the dramatic benefit of using the Lucentis drug in these patients. 00:07:48;13 For the first time, we saw improvement in vision for these patients, where they 00:07:52;15 restored their visual function over three or four months, and this was maintained over two years. 00:07:56;26 Now, a couple of things to point out. 00:07:58;17 In this clinical trial, the patients received the injection of this drug every month 00:08:03;02 for two years, so a total of 24 injections. 00:08:06;08 That's a lot of treatments, so physicians and others immediately started looking for 00:08:11;06 ways that we could reduce this burden and make the treatment more manageable. 00:08:14;28 And this... this slide here, on the top, is showing that when we reduce the frequency 00:08:20;06 of the treatments compared to monthly injection, the lower frequency treatments also have 00:08:26;03 a lower benefit. 00:08:27;27 And the bottom frame, here, is showing a study that I conducted with 14 investigators 00:08:32;27 around the country. 00:08:33;27 And we looked at a cohort of patients from the original Phase 3 clinical trial, 00:08:38;15 and we did an update assessment on them seven years after... seven years afterwards. 00:08:43;22 And the red line shows this. 00:08:45;01 And you can see over the first two years, the patients with monthly injections had 00:08:48;15 a beautiful increase in their vision. 00:08:51;21 But once they stopped the monthly injections, there was a steady decline. 00:08:55;17 And so out... between year three and year seven, there was a very low treatment frequency, 00:09:02;06 that physicians were only electing to inject two times per year for these patients. 00:09:07;01 And on average, there was a loss of the initial benefit, and even a reversal of the benefit, 00:09:12;27 so the patients ended up with a vision that was below their starting baseline. 00:09:16;13 So, a couple things to point out here. 00:09:20;07 Doctors and patients have to face that we cannot limit the number of these injections 00:09:24;02 the way we'd like to. 00:09:25;23 And as this study shows, at least out to seven years, these patients are at risk to lose vision, 00:09:29;26 so that we're going to have to maintain this intensive treatment regimen for 00:09:34;14 at least many years and possibly for lifelong therapy. 00:09:37;17 So, how do we solve this problem? 00:09:40;08 In work... in collaborating with Tejal Desai, we have drawn up some target profiles 00:09:46;23 that we want for this device to have, from the clinician standpoint and from the patient standpoint. 00:09:51;28 We want this to be a device that when we put it into the eye it delivers the drug 00:09:55;24 effectively for at least four to six months. 00:09:58;18 We want to maintain precise concentrations with this drug, so both that we avoid 00:10:02;18 the peaks and we avoid the troughs. 00:10:04;06 But it has another benefit of precisely controlling the kinetics of the drug release with this device 00:10:09;24 in that, because the eye is such a small structure, there are real limits to 00:10:14;06 how much drug that we can put into these devices because the devices have to be kept so small. 00:10:20;17 So, we have to take a very small payload and stretch it out over many months by 00:10:26;21 precisely controlling the drug release. 00:10:27;24 And this is what allows us to maximize a small drug payload. 00:10:32;07 Some other characteristics that we want the device to have. 00:10:34;21 We want this to be an office procedure that's done pretty similarly to what all of us 00:10:38;20 are already doing, an injection... an injectable device that can be done in the office with local anesthesia. 00:10:44;28 The materials for the device should be degradable materials so that we don't have to go in later 00:10:48;28 and remove these devices, or we don't have accumulation of materials in the eye 00:10:54;17 as we treat these patients over the years. 00:10:56;19 And finally, we want this to be a platform for a number of drugs, both for the drugs 00:11:00;20 that we have already available for a number of different diseases and also some of 00:11:05;11 the drugs that are in the pipeline that will allow us to treat... will allow us to treat other diseases 00:11:09;16 in the very near future. 00:11:12;06 So, all of this is by way of an introduction in the clinical background here. 00:11:17;05 And it sets the table for my colleague, Tejal Desai, who will now come in and talk about 00:11:21;20 some of the progress we've made in this translational project. 00:11:24;15 Hi, I'm Tejal Desai, and I'm a professor in Bioengineering and Therapeutic Sciences at UCSF. 00:11:31;16 And I want to continue our discussion on developing new ocular drug delivery systems. 00:11:37;11 As suggested in Part 1, we really have an unmet need in how to develop treatment strategies 00:11:44;17 for delivering drugs to the back of the eye. 00:11:47;18 And my colleague, Dr. Robert Bhisitkul, eloquently described what our unmet need is, 00:11:55;10 in terms of how to get drugs effectively and safely to that region in the eye. 00:11:59;08 What was interesting is that we actually met because he was describing how there were 00:12:05;12 these wonderful drugs that are able to improve ocular vision. 00:12:10;23 And that, really, the way that they administer them are sort of dating back from the 19th century 00:12:16;00 in terms of injecting them with a needle. 00:12:18;25 And so we started talking at a forum that brought together clinical ophthalmologists 00:12:24;05 as well as bioengineers, and realized that there really was a unique opportunity to develop 00:12:30;01 a technology that could more effectively... and have better safety and compliance for 00:12:36;10 the patient. 00:12:37;16 So, where are we in terms of thinking about drug delivery for the eye? 00:12:42;10 There actually are a lot of technologies that have been developed. 00:12:46;02 We have everything from what we call nondegradable implants. 00:12:51;22 These are large devices or cages that are put into the eye. 00:12:56;11 But as you can see, they range from everything from a reservoir to an actual screw that gets 00:13:04;04 screwed into the eye. 00:13:06;13 And they stay there for the lifetime of the patient. 00:13:09;28 So, once you put these types of devices into the eye, they are basically there for the 00:13:16;09 rest of your lifetime. 00:13:17;26 So, one of the things, as Bob mentioned, we wanted to actually develop something 00:13:22;14 that was degradable. 00:13:23;19 So, there also were some advances in biodegradable implants that were placed in the eye. 00:13:30;02 Some of the things like microspheres and smaller pellets have been developed. 00:13:33;27 But all of these systems actually had only been developed for very small molecules 00:13:38;28 being delivered to the eye and could only really last for very short time periods. 00:13:44;00 So as Bob mentioned, we actually needed to develop something that would last at least 00:13:48;15 four to six months, and be able to be... deliver this drug in a very, very precise manner, 00:13:55;24 but then degrade at the end. 00:13:58;06 And none of these systems actually did that. 00:14:00;22 And finally, we saw that there were also some cell-based implants being developed. 00:14:05;12 And again, this was an idea that potentially could have merit in the future, but for 00:14:10;26 actually treating today's patient there was nothing already developed that would treat the unmet need. 00:14:18;09 So, when we think about the landscape and how people are approaching the delivery of 00:14:24;09 drugs to the eye, we really decided that there was an unmet need in developing long-term 00:14:31;25 biologic delivery devices that could be degradable and also injectable. 00:14:38;00 And if you look at this graph, what I'm pointing out here is that topical eye drops 00:14:43;10 -- we sort of think about that as a way to deliver drugs -- can really only last on the order of hours to days. 00:14:50;25 When you think about putting an eye drop into your eye, very little of that medicine actually 00:14:56;04 penetrates deep within the eye. 00:14:58;06 And in fact, eye drops are really limited to very, very small molecules, things that 00:15:03;20 can easily pass through the junctions of the cornea. 00:15:08;08 If we think about things that are being currently injected -- those are the drugs that Bob mentioned, 00:15:15;00 they're the larger antibodies or proteins -- and of course we can deliver them 00:15:20;14 with fairly large amounts, but we do that in a very invasive way. 00:15:26;19 And this is something that, again, we talked about. 00:15:29;02 These are delivered monthly. 00:15:30;08 So, an injection every single month in order to get these larger proteins into the eye. 00:15:36;24 And finally, there are these larger delivery devices that I mentioned. 00:15:41;03 But to date, there is nothing available that can actually deliver large proteins as well as 00:15:48;13 be biodegradable. 00:15:50;26 So, where are we trying to go? 00:15:53;24 We're trying to develop a device that will really marry the best of all of these different technologies, 00:15:58;27 which is something that will sit in the back of the eye, deliver these 00:16:03;03 large and small molecules, but do so in a way that is as easy and safe for the patient, 00:16:10;25 and relatively low invasiveness. 00:16:13;25 Okay, so the question is, how do we control drug levels? 00:16:19;09 It sounds easy. 00:16:20;09 We just want to get the right drug in the right concentration to the right place. 00:16:24;15 But it's not so trivial. 00:16:25;24 And in fact, most drug delivery systems actually give you a lot of drug right away and then 00:16:32;23 over time give you very little amounts of drug. 00:16:35;20 And that's sort of what we think about when we think about conventional drug delivery systems. 00:16:40;19 You have a reservoir with your given drug. 00:16:45;01 And drug comes out of that reservoir based on Fick's law, which essentially says that 00:16:50;24 diffusion is concentration-dependent. 00:16:54;11 So, if I have a lot of molecules on one end, the molecules will diffuse out based on the 00:17:01;24 concentration difference. 00:17:04;11 That tends to give us profiles that look like this, where you have a burst release followed 00:17:09;06 by a plateau. 00:17:11;11 And in the case of the eye, this is not what we want. 00:17:14;23 We actually want a very small amount of drug to be given over a long period of time. 00:17:20;18 So, how can we change these sort of kinetics? 00:17:23;15 Well, it turns out that if you shrink down your reservoir such that you're 1-2 times 00:17:31;20 the molecular diameter of your drug of interest -- so, looking at a panel number two -- 00:17:38;28 you can actually constrain the drug molecules such that they can only come out one at a time. 00:17:45;06 So, if you do that, instead of having burst release, where all the drugs try to get out 00:17:51;20 at the same time, you can only have one drug molecule coming out at any given one time. 00:17:58;22 And the analogy that I like to use is one of a movie theater, where if you have 00:18:04;18 a hundred people in the audience or you have a thousand people in the audience, if there's only 00:18:09;25 one exit door and somebody yells fire and everybody races to get out, actually, the rate of escape 00:18:17;00 or the rate of getting out of that movie theater is not dictated by how many people are concentrated 00:18:23;13 in the theater. 00:18:24;13 It's really dictated by how many people can escape out that door. 00:18:28;26 And if only one person can come out, then only... the rate is only dependent on 00:18:35;09 how long it takes for all of those people to get out. 00:18:38;24 So, we apply that same principle, and we are able to get these very linear release rates. 00:18:44;18 And if we create very many tiny nanoscale pores, what we can then do is tune that 00:18:51;03 release rate up and down. 00:18:53;16 And that's what we employ for designing our drug delivery systems. 00:18:57;24 So, how do we do that? 00:18:59;28 Well, my lab and many of my colleagues have been working to develop materials in which 00:19:05;14 we can precisely create nanopores. 00:19:09;04 And just an example, these are some of the materials that we've worked on in the past, 00:19:13;17 ranging from nanoporous alumina, nanoporous silicon, as well as titanium. 00:19:20;17 And as you can see, there are very, very defined architectures that are made in all of these materials. 00:19:27;16 And we can control the pore size from anything from a couple of nanometers up to 00:19:32;09 hundreds of nanometers or even microns. 00:19:35;05 And what's unique about these materials is that they don't have what we call a pore size 00:19:39;15 distribution. 00:19:40;19 So, whatever we design, every single pore has the same size. 00:19:45;25 And this is important for sort of taking advantage of that effect I mentioned and getting 00:19:50;24 a very, very linear profile. 00:19:55;06 How linear is this profile? 00:19:57;06 Well, for example, if we wanted to deliver something like albumin 00:20:01;27 -- this is a protein that has a molecular weight of about 66,000 -- 00:20:06;27 we can essentially design pore sizes that 00:20:09;15 are anywhere from 30 nanometers down to 13 nanometers. 00:20:15;03 And if you take a look at the graph on the top, what that's showing you is just the difference 00:20:20;14 from going from a sort of conventional Fickian type of arrangement, where you actually see 00:20:28;11 this burst release, to something that's much more linear. 00:20:34;14 And when you get down to interferon, which is even smaller 00:20:38;14 -- down to about 19,000 molecular weight -- 00:20:41;02 we have to really go down to nanometer-sized pores that are on the order of 10-13 nanometers 00:20:47;03 to get that linear release. 00:20:48;21 So, by thinking about what molecule we're interested in, we can design a pore size 00:20:54;18 that precisely fits that molecule and gives us this linear profile. 00:20:58;13 So, why do we care? 00:21:03;02 As we keep mentioning, getting into this precise rate of release gives us what we call a therapeutic window. 00:21:12;24 So, instead of giving a lot of drug, and having wastage of drug, and actually having 00:21:19;18 side effects from overdosing, what we get is something that gives us just enough drug to be 00:21:27;03 physiologically effective and treat the disease but doesn't give us the toxicity that's associated 00:21:32;15 with a lot of drug, and also is not subtherapeutic. 00:21:35;08 So, we're actually giving something that's right in the region that we want. 00:21:40;21 So, forgetting the highs and lows that are associated with injection, and really going 00:21:46;00 into what we call the therapeutic window. 00:21:49;17 So, one of the challenges with sort of thinking about the eye was mentioned by Bob as well, 00:21:58;15 and that was that this is a pretty small space. 00:22:02;01 We really can't think about a large implant that sits in the eye and bounces around. 00:22:08;02 It has to be an implant that's relatively thin, transparent, flexible, and can be injected 00:22:15;04 via a needle. 00:22:16;26 And most of the work that people have done in terms of creating nanoporous materials 00:22:20;25 has conventionally been done in inorganic materials, so the ceramics and some of 00:22:26;20 the metal oxides that I mentioned earlier. 00:22:29;14 And so our challenge was, how could we actually create very small pores in a thin, flexible material, 00:22:36;12 almost like a contact lens type of material? 00:22:39;23 So, what we ended up doing is actually developing... developed a technique called nanotemplating. 00:22:46;22 And so this is actually pretty simple to understand. 00:22:50;08 It's really sort of creating a replica of a mold. 00:22:54;04 But instead of something on a large scale, what we're doing is creating a very, very 00:22:58;11 small structure and then replicating that off of a different material. 00:23:03;07 So, for example, in this image what we're showing is an inorganic porous material 00:23:11;23 -- so, this is the picture shown here, this is nanopores -- and then if we press another material, 00:23:19;27 a polymer or a soft material on those pores, what we get is the inverse of that structure. 00:23:26;09 And in this case, these are nanowires that project out of the surface. 00:23:31;01 And so, we.... as you can see, we get very precise structures by using this method. 00:23:36;23 So, we can do the opposite, which is we can create nanowires and then template off 00:23:45;01 a soft material and create nanopores. 00:23:49;12 And this is what we did. 00:23:50;28 We actually developed a process where we can create very thin films of nanoporous polymers 00:23:57;13 from nanorod templates. 00:24:00;02 And the details of this process are not necessarily important except for the fact that 00:24:07;14 if you look here what we're essentially doing is we're growing these rods. 00:24:12;14 And these rods can be controlled in terms of their width, their diameter, their spacing. 00:24:19;10 We then spin a thin film. 00:24:22;07 This can be any polymer of interest. 00:24:24;03 We've been using something called polycaprolactone. 00:24:27;11 This is a biodegradable polymer, and it's very flexible and robust. 00:24:32;22 And then we basically sandwich that between a structural layer that will hold it in place, 00:24:39;05 because if we have a very, very porous layer it may be too fragile. 00:24:42;17 So, we sort of sandwich multiple layers to create something that a surgeon can actually manipulate. 00:24:49;08 One of the things within our field of nanotechnology is that we want to create things that are 00:24:55;07 easily adaptable by the clinician. 00:24:58;23 And so, again, really thinking about creating a structure but then adapting that structure 00:25:03;17 in a way that could be administered in the clinic. 00:25:07;14 What does this look like? 00:25:08;26 Well, before, if you look at the rods, you can see they have all of this morphology of 00:25:15;09 things sticking out of the surface. 00:25:19;09 But when you look at the pores, it's the inverse of that. 00:25:22;10 So, we can do that essentially with any structure. 00:25:27;10 And after we do that, what we get are these thin films. 00:25:31;03 And you can see from looking at the image, the actual nanoporous region is this one 00:25:36;07 that's sort of the opaque area within the film. 00:25:39;26 When it gets hydrated, it actually becomes transparent. 00:25:43;00 But the nice thing about these films is they're actually very rollable or foldable. 00:25:48;18 They can actually fit into a needle. 00:25:51;22 And that's the same needle that is used today in the clinic. 00:25:54;27 So, we can take... con... you know, conceptually, we can take these films and put them 00:25:59;18 into a needle that every ophthalmologist is already familiar with using. 00:26:06;01 Now, if we take an electron microscope and we zoom into what that structure is, 00:26:14;04 of that porous area, what we see is that we have a whole region which is essentially 00:26:23;01 a microporous region, this sort of area, here. 00:26:26;23 And then if you zoom in, what you see is there is this nanoporous region. 00:26:31;26 And this nanoporous region is really the rate-limiting... limiting region. 00:26:36;09 That's the region that's going to constrain our molecules and keep our molecules 00:26:39;25 coming out one at a time at a very precise rate. 00:26:47;15 How do we make this a device? 00:26:49;06 Well, we spent a lot of time thinking about, how do you put in a drug, keep that drug stable, 00:26:56;13 maintain bioactivity, and then have this as a device that can be put into the body? 00:27:01;20 And so what we came up with was a method to take two of those thin films that we create 00:27:07;26 through that templating technique, basically encapsulate a drug around that film 00:27:14;08 -- so, the red dot in this schematic is the drug that we can either pellet or we can put that 00:27:19;21 in a powder or a liquid solution -- and we then bring the two films together, 00:27:26;15 and we do that, basically, by holding two weights and bringing the films and then heat sealing those films. 00:27:32;27 And what we end up with is basically a device that has the drug cargo in the middle, 00:27:40;11 but it's essentially a very thin, flexible film. 00:27:43;04 The shape, the size, the actual morphology of the film can be changed very easily. 00:27:51;26 And so, as we sort of talked about earlier, this can be adapted to a range of 00:27:57;00 different drugs and a range of different durations. 00:27:59;14 If we want something to last for one month versus four months versus two years, we can 00:28:05;10 simply change the size or the porosity of those films. 00:28:12;17 What does that get us, doing all this nanotemplating? 00:28:15;09 Well, what it does is it gives us that very, very precise control of drug release. 00:28:22;22 So, these are two graphs. 00:28:24;27 This is just showing a model protein, which is bovine serum albumin. 00:28:29;24 And what I'm showing you is, on top, basically release date... release rate per day. 00:28:36;07 So, this is over 200 days, so greater than 4 months. 00:28:41;20 And essentially what you're seeing is that the release rate of these devices stays between 00:28:47;23 1 and 2 micrograms per day. 00:28:51;14 And that goes out all the way across those 200 days. 00:28:55;09 So, if we want 10 micrograms per day, we can dial it in to make it 10 micrograms 00:29:00;22 being released over that duration. 00:29:02;10 If we want something smaller, we can dial it in. 00:29:05;04 But the important thing is that we can take what was a once-a-month payload, 00:29:11;12 which is 500 micrograms, and essentially make that last for 4 to 6 months. 00:29:17;13 So, given the current clinical standard of care, where we're injecting a bolus of 00:29:24;15 500 micrograms, this is the same amount of drug -- so we don't worry about toxicity -- 00:29:29;13 but we're extending or stretching as was mentioned in the earlier presentation the drug profile 00:29:35;17 out to several months. 00:29:40;03 We can do this with Lucentis. 00:29:41;06 So, this is that great drug that is able to actually improve visual acuity. 00:29:48;01 And again, you see this linear release. 00:29:51;02 The release is shown over about 120 days, but it continues up until the end of the payload. 00:29:58;15 And one of the things that's very nice about this approach is that we're decoupling 00:30:03;19 the formulation of the drug with the actual kinetics of the drug delivery system. 00:30:08;18 And so that allows us to have a very, very high stability. 00:30:11;22 And we can keep the drug stable and pure. 00:30:16;00 And we can release it at a predetermined rate. 00:30:21;12 How would this be administered? 00:30:23;00 Well, again, knowing that in the clinic Lucentis is injected via a needle, we really wanted 00:30:30;02 to make this device flexible and able to be placed in those same types of needles. 00:30:36;22 And so, here is an example where we're actually taking our device, we're putting it into a needle, 00:30:41;11 and we're injecting it into the back of the eye, in this case in rabbits. 00:30:46;22 And you can see what that looks like. 00:30:50;03 Keep in mind this is a graduate student who's trying to get that film into... into the needle. 00:30:56;20 But as you see, we're holding open the eye. 00:31:00;19 We're doing an injection. 00:31:01;22 This is very similar to what is done in the clinic. 00:31:06;08 And we put that in there, we press it, and then we take the needle out. 00:31:11;21 And if you look very carefully through that magnifying glass that's sitting right on top 00:31:16;26 of the eye, you can make out the corner of that film. 00:31:20;08 It is transparent, but it sits in the peripheral vitreous, and it's able to elute drug over time. 00:31:30;11 In vivo, we also see that these things are able to release in that linear fashion. 00:31:36;06 So, these are, again, some examples in a study in which we basically took devices that were 00:31:42;26 sitting in vitro and releasing drug, and then we took those same devices and we put them 00:31:47;17 into the rabbit eye. 00:31:49;04 And we wanted to ask the question, can these devices release in a consistent manner to 00:31:54;04 what we saw in vitro? 00:31:55;26 And what we saw is, yes. 00:31:58;00 We can continue that profile out. 00:32:01;10 And as compared to an injection, as you see here, we're continuing to have drug 00:32:08;17 being released, whereas in an injection basically the drug amounts go back to zero very rapidly. 00:32:15;26 So, we're really excited about thinking about a new way that we can deliver these proteins 00:32:23;08 and biologics in a way that, again, is safe for the patient but also improves patient compliance. 00:32:31;04 And really, we think, might help the visual outcomes by having a continuous therapeutic dose 00:32:38;06 of our intended drug target. 00:32:42;12 One of the things that we have really focused on is the safety and biocompatibility of 00:32:48;05 this type of device. 00:32:49;22 And this is just a little bit of data showing that putting in a polymer film and 00:32:56;10 having it sit there for a period of 6 and even 12 months really minimally disturbs 00:33:03;01 the back of the eye in terms of the histology of the retina or any other parts of the eye. 00:33:08;27 And what we see is very similar to control eyes in which we place no device. 00:33:15;25 And this is important because, again, if we're going to release a drug that's supposed 00:33:20;13 to be therapeutic, we don't want to induce any other complications. 00:33:25;23 So, our goal with this collaboration, and I think again the beauty of bringing together 00:33:32;27 clinicians and engineers or other people interested in developing technologies, is that we can 00:33:39;01 focus on unmet clinical needs and, in this case, really improving how ocular drugs are delivered. 00:33:46;24 And do that in a way that can, we hope, change the course of administration for not 00:33:52;25 just drugs for the back of the eye but also drugs for other parts of the body. 00:33:57;26 This is a platform technology, and we hope it can be used for the delivery of biologics 00:34:03;13 as well as small molecules to many port... many different places in the body. 00:34:07;22 So, where is the future? 00:34:10;12 Well, we're actively seeking to scale this device up and hope that we can put this 00:34:17;00 into patients at some point in the near future. 00:34:20;09 We hope that this technology will really lead to a future where patients have access to 00:34:26;28 a better visual outcome. 00:34:30;08 And with this I'd like to thank our funders, including the NIH, the Coulter Foundation, 00:34:36;16 the Rogers Foundation, and the UCSF Catalyst Award for funding the collaboration 00:34:43;13 and the innovation that came through this.