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“New Treatments for Age-Related Macular Degeneration: Drug, Genes & Stem Cells”-Dr. Marco Zarbin

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The invited speaker at the July 5, 2022 meeting of the Old Guard of Summit NJ was Dr. Marco Zarbin who discussed how age-related macular degeneration (AMD) is the leading cause of blindness among persons over 55, and the range of new treatments that are available and coming in the near future. Thirty percent of those over 70 have some signs of the condition.

Dr. Zarbin is a leading macular degeneration specialist and co-director of the Ocular Cell Transplantation Laboratory at Rutgers NJMS. He graduated Phi Beta Kappa from Dartmouth and received MD and PhD degrees from Johns Hopkins.

Credit: Old Guard Summit

Video Transcript:

So we’ve got a real special treat today we’ve got but we’ve got my classmate from the accomplished and generous class of 1978 at dartmouth college that should be enough for you but uh uh i’m going to give you uh the details uh so it’s dr marco zarbit who received his ba uh in biochemistry from dartmouth where he was phi beta kappa subah [ __ ] laude with highest distinction in 1978. he’s taking better care of himself than i have uh he later attended johns hopkins and was awarded degrees in medicine in pharmacology and graduated as a member of the alpha omega alpha honor society dr zarbin did his residency also at johns hopkins completing fellowships in vitriol retinal surgery and in medical retinal disease dr zarban served as the assistant professor of ophthalmology at the university of california in san francisco and is chief of the division of ophthalmology at the department of veterans affairs also in san francisco he was appointed chair of the institute again of optomology and visual science at rutgers our state university and chief ophthalmology at university hospital in newark he has the alphonse osnothe md lions eye research professor of ophthalmology and neurosci science also there he’s co-director of the ocular cell transportation laboratory at rutgers his research is focused on surgical treatments for age-related macular degeneration which is you know the leading cause of blindness in persons over age 55 in the united states if you know anyone like that this research which involves the transplantation of specialized cells has been supported by grants from numerous foundations he’s also written extensively in the in the field he’s past president of the board of trustees the association of university professors of ophthalmology editor-in-chief of translation vision science and technology and a member of the editorial boards of ophthalmology in the asia pacific journal of ophthalmology he’s received so many awards i can’t list them all here but they include the life achievement honor award from the american academy of ophthalmology and he’s received an honor award from the american society of retina specials he has been listed among the best doctors in the new york area since 1996.

Without further ado i present to you dr mark ozarko [Applause] thank you really for a very generous introduction jody um i want to ask two questions before i get started um first how many of you here know someone who’s getting treated for age-related macular degeneration a lot okay that’s what i expect second question how many of you have a background in biology one two and i know i you do too so that this determines whether i’m going to show a particular slide or not but my senses that we have a very strongly educated group of people here so if you give me a minute there’s a slide that i wasn’t going to show that i’m now going to turn on because you might find it interesting and then i’ll and then i’ll start the talk um and the talk is about 55 minutes um and so i think that will leave time for questions should you have any bear with me please for a moment so uh today i’m going to talk about age-related macular degeneration it’s pathogenesis and therapy and these are my financial disclosures all of which are relevant in some way or another to the talk but in fact they’re only relevant in principles but not in reality i’m going to first describe through the ocular anatomy because i think you can’t really understand um the stages of the disease and certainly can’t understand the basis of the treatment for the disease without understanding the anatomy and um and that’ll be pretty straightforward and then i’m going to define the disease and show you the clinical manifestations many of which you’ve probably heard of but but you may not actually know what those manifestations are in fact and that sets up an explanation for the pathogenesis which in turn is the basis for the therapy and that is also the basis for understanding what the therapies in development are based on so first the anatomy and now the external anatomy that is familiar to everybody uh the white part of the eye is the sclera then the clear part of the eye is the cornea uh the colored part of the eye is the iris and then that hole in the iris is called the pupil now the this is obviously the eye in the orbital socket uh looking from the side and if we were to cut the eye in half you’d see this cross-sectional image and what i want to focus on now is the cross-sectional image of the eyeball itself uh and here you can see the clear front part of the cornea uh behind which is the lens and as you probably know the cornea and the lens are important for focusing light uh on the retina then you have this clear gelatinous material called the vitreous which occupies about four-fifths of the vine of the globe uh and then the next thing we’ll encounter is the retina which is the actual neural tissue in the eye and that contains the light sensing cells that convert electromagnetic energy to electrochemical energy and then because of processing that occurs in the retina we convert that into a series of on off signals and i think there are a number of engineers in the room so that’ll kind of make sense to you now external to the retina is a vascular layer called the choroid this is a little bit counter-intuitive but it turns out that the retina has two sources of blood flow one which is shown well here which is the external source called the choroid it supplies the outer one through the retina and another which isn’t shown well in this picture uh let’s see if my cursor shows up here um it does it’s but it’s an inner layer of vessels called the retinal blood vessels uh and then external record is the white part of the eye which is the splitter which is essentially sinew that protects the internal structures and then these on off signals that are generated through image processing leave the retina and the eye through a structure called the optic nerve and uh and from there it goes to various nuclei in our central nervous system but the retina is part of the central nervous system so this is actually a picture of a cadaver eye obviously a human cadaver eye and you can see the lens and you can see the retina and then there’s this area in between the two which doesn’t contain any neural tissue called the pars plana and it’s through that area for any of you who get injections or who know people who get the injections in their eye the needle goes through the parse planus so that it won’t damage the lens or the retina and if any of you by chance have received a sustained delivery system that’s also implanted through the porous planar uh okay now the retina lines the inner two thirds of the eyeball but the part of the retina that subserves very high acuity vision uh comprises a very small fraction of the total surface area and that’s called a macula and i’m going to show you what this looks like clinically in a fundus photograph so this is a picture of the back of the eye focusing on the macula but just so for clarity you can see this rather thin retinal artery a thicker retinal vein this is what the optic nerve like looks like when you look at it on fuss and then there’s the macula which is a specialized region of the retina but the most important part of the macula is the very center and that’s the phobia the fovea is the part of the eye that creates high acuity vision which we use to recognize faces to read to thread a needle to do surgery if you shoot sporting plays when you’re looking at that clay that bird that’s what you’re looking with the phobia and and to understand to have a deep understanding of what i’m about to talk about we need to look at the structure of the fovea at the level of resolution of like microscopy so that’s what i’m going to show you now which is to orient you the neural tissue is shown the retina and you’ll notice that the retina has these purple dots these are different layers of cells and the the layer of cells that we’re going to be focusing on are the photoreceptors then the layer external to the retina as i mentioned before is the chloride it’s a vascular layer which supplies the outer third of the retina and then you can see the sclera but i’m showing you this picture to show you the retina and you can see the macula is a much larger surface area in fact this this slide inaccurately demonstrates the full extent of the macula but it’s a much larger surface area than the surface area of the phobia and just by looking at this picture you can see what’s special about the phobia there are no cells in front of the photoreceptors um and so in the very center of uh the phobia the photoreceptors are highly specialized there are type of photoreceptor called cones which in fact are specialized and they are what we use to see well in conditions of bright light whereas if we move off to the side away from the phobial center we have rods and cones and of course as you know rods uh help us in conditions of dim elimination uh to see now the next slide i i’m showing to illustrate the relationship between location in the retina and visual acuity so uh to remind you uh we have uh the cones dead center and on the left is a plot uh it’s a plot of visual acuity on the y-axis as a function of location on the x-axis and the zero degree location is the phobia and so i’ve shown you the corresponding regions with the red arrows and that almost discontinuous peak uh in the phobia in terms of visual acuity that’s dead center so the point here is that as you move away from the phobial center visual acuity drops off exponentially and that’s why you could have damage to just a 250 micron region of your retina but if it involves a foliar your vision is going to decrease from 2020 to 2200 or 2400 which is the level of blindness now underneath the photoreceptors is a layer of tissue uh called the retinal pigment epithelium and it’s a pigmented layer of cells that i’m going to show you in schematic form in the next slide um so the rpe cells are cuboidal they contain pigment and their function is essentially to nourish the photoreceptors and they reside on a surface of connective tissue called brooks membrane now just to remind you external to the rpe and the brooks membrane is the choroid uh which is a vascular layer that supplies the blood flow to the rp and foot receptors now it is a remarkable fact that we can image the retina in a living patient at the level of resolution of life microscopy and it’s a very important fact otherwise we wouldn’t be able to do the treatment for the wet form of immaculate degeneration properly so on the top i’m showing you the histology of the of the phobia uh and on the body uh an image of a different patient obviously because this patient on the bottom is alive the one on the top is dead uh but it’s an image that’s created with a technology known as optical coherence tomography which essentially um is um taking advantage of the different refractive properties of different layers of the retina and you shoot in a long wavelength flight you get a pattern uh a diffraction pattern back and then you can actually reconstruct the different layers that way mathematically but just to give you a sense of the resolution of the system uh you see that the foveal photoreceptors pointed out with the red arrow those photoreceptors are evident in the red arrow in the oct image there’s a part of the of the photoreceptor that’s very enriched in mitochondria called the ellipsoid which you can see in the histology and you can see that where in this picture it’s that bright band and then there’s a part of the uh the retinal pigment epithelium uh which is that pigmented there in the picture and you can see that then uh which is a second bright band in the oct image so this this works trivially at the level of resolution of three microns so you can even with certain refinements get higher level resolution so i haven’t told you how we see and that’s not the purpose of this talk but it seems like it’s appropriate at least in a very superficial way to explain it um at least as far as i understand it so you have light reflected off an object uh externally that light gets focused by the cornea and the lens into a real inverted image uh on the surface of your retina and then of course uh that electromagnetic energy is what excites the photoreceptors uh to generate this electrochemical signal um which is the uh uh greater action it leads to a change in the membrane potential of the second order neuron and this is where the magic happens that image gets deconstructed in various ways it gets deconstructed with regard to edges rate of movement of edges contrast color it’s uh it’s like taking apart a sentence if you ever had to do that when you were [Music] and that deconstruction is essentially a series of ones and zeros that leaves your eye through the optic nerve and goes into the brain and it first goes to the lateral geniculate nucleus which is about here deep and then to the back to the striate cortex and the occipital region and then the whole thing gets reassembled through the parietal cortex and the temporal parietal cortex and it’s somewhere here in our brain inside my skull about this level that we actually see seeing does not happen and okay so now for age-related macular degeneration so you know first i’m going to define it and maybe it won’t make any sense to you and then i’m going to show you what i mean and then i’m going to show you the definition again so hopefully that would make you feel like you’ve learned something so it’s a condition that’s characterized by the accumulation of abnormal debris actually membranous debris external to the retinal pigment epithelium and the clinical manifestations of the disease are jerusalem atrophy which is death or degeneration of the photoreceptors the retinal pigment epithelium and the courier capillaris detachment of the retinal pigment epithelium from brook’s membrane and then coronal new vessel formation which you probably know is what amd and this uh typically once that after age 50 uh as you uh as jody mentioned it’s the major still the major cause of blindness in persons over age 55 in the industrialized world prevalence of about eighteen percent so one in five people that’s why i was pretty certain that just about everyone here would know someone that had the disease or actually now what are jerusalem they are the hallmark of the early and intermediate stages of the disease what do they look like well that’s shown in this picture they look like these yellow spots under the retina and we can image what they look like using the oct machine and that’s shown in panel d of this photograph um you can see how that hyper reflective rp blend band is elevated uh off of the brooks membrane surface and that that material that’s elevating it is the druzanoid material and uh to show you what it really looks like i’m going to compare the histology with an oct image so histologically you can see the photoreceptors the little purple circles are the cell bodies uh and the areas here i guess i need to move this this uh this area is the finger like like the teeth of a comb that project from the cell bodies of the photoreceptors and that that part of the retina is known as the outer segment of the photoreceptors and that’s where the light capture the photon capture occurs uh and and with this level of magnification of the oct uh you can’t really see the photoreceptors with that level of detail um although you did in the previous image that i showed you uh then we have the retinal pigment epithelium which is evident in the oct image as that hyperreflective band and then you have the abnormal debris underneath the rectal pigment epithelium which is very easy to see in this quite large trees normally they’re not this large but it makes for a nice illustration now um in the late stages of the disease i’ve showed you the early intermediate stage what do the late stages look like well there are two different manifestations one probably you know is wet amd which is actually collodion vessel growth under the retina and that’s shown here um where you have a perot new vessel and the problem with these things is they create scar tissue they bleed and leak fluid and then the other type of manifestation known as dry amd which is very misleading terminology uh what we call geographic atrophy technically and in geographic atrophy you see this clearly abnormal area although you may not be able to articulate what’s abnormal about it but if you look outside the area of atrophy you see that sort of sunset glow orange that color is due to the pigment in the retinal pigment epithelium so in the area of atrophy where you’re missing that color it’s because the rp cells have died not only that i don’t think you need a degree in biology to see that you’re looking at larger vessels in that area what are those those are the larger coral vessels why can you see them you can see them for two reasons first because the rp cells are dead and gone and second because of corey capillaris which are capillaries of atrophy leaving behind only the profused larger vessels and so a simple minor way of thinking about wet amd is that you have the presence of abnormal tissue that causes blindness and in advanced dry amd you have the absence of normal tissue that causes blindness how do you get one versus the other we’re going to talk about that now here’s a patient uh who has wet a and b and i’ve actually shown you something similar but let me show you how we image such a patient how we visualize the abnormal vessels the traditional way is to inject a dye called fluorescein into an arm vein and take pictures of the back of the eye and this dye fluoresces and so with the right filters you can capture the emitted fluorescence energy and the dye tends to accumulate in the abnormal vessels which makes the abnormal vessels look bright but we don’t need to do that in many many cases in in most cases all we need to do is an oct image and what we’ll see uh with an oct image is that elevation of the rpe cells but the material elevating it has a higher uh optical density than jerusalem and so we can usually identify the corroded vessels that way now um we can similarly image the presence of atrophy now on the left is a normal phobia and that bracket’s showing the thickness of the photoreceptor learn the phobia but in a person who’s got advanced dry amd which is shown on the right uh you can see there’s virtually no photoreceptors left so this is how we actually examine the patients uh to figure out what to do for them um now there’s this um sort of mythology that seems to have arisen which is that you either have the wet amd or the advanced triangle that’s simply not true and in fact if you look histologically about third of the patients have both conditions here’s a patient because an example of having health conditions this person has drusen those yellow spots the person has atrophy where you can see through the pigment epithelium and they also have a corona vessel now how do i know that because that little red spot is a hemorrhage and that’s usually a sign of according to vessels so these things can coexist so now i’m going to show you the definition again it’s characterized by the accumulation of membranous material under the retinal pigment epithelium the clinical manifestations of jerusalem atrophy the photoreceptors are the emperor capillaris rp detachment coronal vessel formation hopefully you now know what each of those things mean now the real question is why does all this and there are competing theories about this i think the simplest you know newton’s law of gravity works pretty well you don’t need to use general relativity to do most calculations that kind of simplification is what i’m going to apply here i’m going to simplify the pathogenesis in a way that basically works pretty well by saying inflammation uncontrolled inflammation causes damage to the cardio capillaries and the retinal pigment epithelium and that’s what causes these changes and um when you get this chronic inflammation you get damage to the core capillaries and why is that important the photoreceptors of the retina are among actually they have the highest oxygen consumption of any tissue in your body and in fact for those of you with a biological background you know that generally um when you have oxygen present and they have a very high blood flow through choroid you you you create energy with oxidative phosphorylation but in conditions of hypoxia that is low oxygen levels you create energy using glycolysis well the photoreceptors operate under conditions of aerobic glycolysis which is shocking it means they’re always operating on the edge of hypoxia so if you lose capital capillaries from inflammation you’ve immediately compromised rpe and photoreceptor function and eventually you could kill those cells uh and and um and you get abnormal blood vessels growth also when you have the choreocapillar established i’m going to tell you a little bit more about that although your intuition will already tell you why that happens um the the way i think about the coronal new blood vessel growth is it’s what is called a homeostatic response so um homeostatic response we could say is a healing response naturally when your body gets injured it doesn’t just sit there you know when you cut your finger um if you study it you’ll notice a couple of things happening uh first the margin of the incision gets pink that’s from the new blood vessel goes then it becomes irregular that’s because of contraction of the tissue that’s actually filling in the mood and then eventually with good mood healing uh you don’t see that you don’t see the scar anymore although there are some people that have a lot of scars which are called keywords well coronavascularization is a homeostatic response to aesthemia induced by for capillaries damage and just to remind you uh the retina has two sources of blood supply the inner two-thirds are supplied by the retinal vessels the outer uh one-third supplied by the coronal vessels and the coronal vessels are the primary site of damage in my opinion in age-related macular degeneration um i want to show you why i think that using human histology and to do that i’m first going to show you what the architecture of the quarter capillaries is it’s a sinusoidal system you know it’s not like input from the artery to arterial to capillary to manual to vein that’s not how sinusoidal systems operate it’s artery arterial to a network of connected capillaries to venule to the so here is a as an electron micrograph or corrodologic and uh you can see the arterial that feeds this cluster of connected choreo capillaries and the blood flows from the arteriole through those vascular channels and then leaves up through the manual it’s really pretty straightforward but it’s very helpful to have that image in your head now i’m going to show you the picture of an older person without amd so panel a over here is their clinical fundus photograph then they die and you have these fundus photographs postmortem and you can remove the retina and image the choreo capillaries with a very special stain that makes them look red and if you do that uh what you’ll see uh is the normal choriocapillaris under the phobia and just to remind you um if you look at these little vascular channels which are the capillaries you can see them outlined with a red stain that’s normal that’s the way we all hope to look uh when we’re 87.

um okay but now somebody is not so lucky uh this is an 86 year old woman who had early age-related macular degeneration it’s the same sequence her clinical photograph her postmortem photograph and now we’re going to look in her macula at the quarter capillaries and the first thing i’m sure you can all see is it’s dark it’s dark because there’s not much red stain there’s not much red stain because there is a great reduction in the choreocapillary density and if you look under high magnification that’s very obvious because those asterisks that you see in the picture are areas where there are simply no choreo capillaries and as i told you when you’re working in a condition of vaporic with glycolysis you can’t afford to lose very many capillaries before you have a problem uh and and uh just to convince you that this is really a macular problem if you look nearby uh but not under the macula the quarter capillaries are pretty normal what’s really interesting is that if you look at the edge of those areas of corey capillary dropout you see these areas of intense red staining those are shown under high magnification the panel f over here and what those are are little buds of new blood vessels growing and that’s why i think that corona vascularization is an omniscient response to ischemia induced by course capillaries okay let’s look directly now at a patient that has it invested and see what that looks like well i’ve shown you this patient already this is the one with the fluorescein angiogram and the oct image and if you look uh again focusing on their capillaries using that red stain you can see the coronal new vessel it almost looks like a c fan gragonia fabela you know one of those things you find in the caribbean um and if you look under high magnification at the edge of the corroding vessel that’s what you’ll see in panel f and you can see that there’s bright red standing where the new vessel is and right outside of it it’s very dark even with an asterisk showing there’s no quarter capillaries that’s another sign that these things grow in response to ischemia and in contrast if you look outside the molecule of the query capillaries density as well okay so the way i think we should think about um coordinate vascularization or white amd is that it’s a pathologic vascular uh growth but it’s in response to an out of coronal blood flow so we want the blood vessels to grow in response to ischemia but these blood vessels are immature and they don’t behave properly and that’s why they create a problem and that’s the basis for several therapies that i’m going to describe is how to fix that in maturity uh in the case of the geographic atrophy um let’s see if i get it to come up there the problem is the inadequate uh quarter capillary’s blood flow causes that the photoreceptors in fact what we should ask ourselves is why does everybody get coronal vascularization and i don’t know the answer to that question uh now i haven’t said why there’s this inflammation in the core of capillaries and again this is a matter of some controversy i can tell you that a highly metabolically active barriers are going to generate reactive oxygen species reactive oxygen species are going to damage cellular structures damage dna uh and that’s cellular damage can create an inflammatory response but uh that happens in all of us as we get older and yet we don’t all get age-related degeneration i think the thing that leads in some people to getting the disease is what’s called complement dysregulation i realize that most of you have not had a background in biology so i’m going to take a minute here the compliment system has it’s a it’s the ancient uh basis of immunity in us okay it’s the first source of immunity as we evolved and there are four different ways it can be activated uh they’re called the classical the lectin and the alternative pathway and there’s actually the fourth way which i’m not illustrating which is the extrinsic pathway now um as i mentioned to you complement activation is really important for cellular for for our immune status and it’s so important that it’s actually chronically activated but we regulate it and the reason it’s chronically activated at a low level is that if some bacteria or virus invades us you can get this massive acceleration of the complement activation system really really rapid uh and it also helps our body clear the dead and damaged cells well the problem arises when you have inappropriate uh activation of the complement system or dysregulation system and actually this problem is known to cause several different kinds of diseases for example there’s a type of kidney disease called type three glomerulonerolitis which is due to inappropriate complement activation there’s a disease called paroxysmal nocturnal hemoglobin oreo which is associated with inappropriate compliment activation there’s probably even some link to alzheimer’s disease in complement dysregulation um and as you might expect i wouldn’t be talking about this unless there have been documented mutations in patients with amd in the computer regulatory system and one or two all these green circles show areas where there are documented mutations and patients with a and b in the complement system and so uh the the thing from a pathway perspective which is important for drug design uh to understand is that no matter which pathway of activation activates the system they all converge on this one molecule called c3 and when c3 is hydrolyzed or cleaved shall we say we form two components uh one is c3a which actually incites an additional inflammatory response and one is c3b and c3b hydrolyzes the second key component which is c5 into two components c5a which also incites a massive inflammatory response and c5b and c5b combines with other components of the complement system to call to create what’s called the membrane attack complex but what it really is is it’s poor it’s a poor in the cell membrane and once you make enough of these pores the cell can no longer regulate water passage into it and it swells ruptures and dies and when it’s the bacterium cell we like it when it’s our cell we don’t just to show you not making this up this is some histology of a patient with amd the red stain on the left is standing complement factor five you can see it’s present uh in jerusalem it’s present in that abnormal material under the retinal pigment epithelium and the membrane attack complex is present in rpe cells and also in jerusalem uh underneath the rectal pigment epithelium and what you can’t see quite as clearly is that both of these components are also present in the core capillaries so um i think this point may be subtle but it’s it may not be subtle to you the current therapy for coronal neovascularization actually doesn’t target the true cause of coronary vascularization because the true cause as i’ve hypothesized with you is queer capitalist damage and quarter capillaries damage leads to this ischemia and hypoxia and that leads to the production of a molecule called hypoxia factor which in turn leads to altered dna expression in our cells where we start producing a molecule that is called vascular endothelial growth factor in its vascular endothelial growth factor that our current therapy is targeted against and that is what people have been getting injections of anti-vegf agents they’ve been getting injections in their eye for what amd probably since 2005 or six depending on whether they were enrolled in clinical trials and it works really well so it’s imperfect but it works very well um now in order to understand exactly why we do anti-budget therapy and more importantly what the new therapies are going to look like i want to show you a little bit about blood vessel growth so you know blood vessels capillaries are basically comprised comprising two cells there’s the endothelial cells behind and then there’s these cells on the outside called the parasites uh that line the wall and you need both of those cells in order to have blood vessels that both deliver blood and they don’t leak fluid and they don’t leak red blood cells which is very bad and when we have a condition of hypoxia as i mentioned to you the body starts making vascular endothelial growth factor which induces a change in the structure of the capillaries it causes the parasites to go away and the endothelial cells have receptors for the egf and they start growing out uh towards the degf and the process that’s known as tip selection and so you have some cells that end up being stock cells some cells that are the big tip cells and this whole process uh matures into a situation called vessel sprouting and the vessel sprouts uh eventually the nastiness and when things are going the way they’re supposed to you get a mature blood vessel and um the mature blood vessel doesn’t happen you know by magic it happens because there’s a change in the expression of certain chemicals of our cells one of which is called ancient one which causes the parasites to be established and you know we get this stable mature vascular network and that’s like your finger healing from the cut but the problem in age-related macular degeneration is that that’s not what happens uh what happens is we get the vascular endothelial growth factor production which causes the immature blood vessels to grow but what we don’t get in most patients is the maturing part of the process where you have venture to eat an expression and so these immature blood vessels leave blood and fluid okay um so now we can talk about the therapy and why we do it and how it works and how it doesn’t work so for wet amd um there is uh treatment that blocks the effects of the egf and those are the standard injections that i’ll mention there’s a sustained delivery system called the poor delivery system that’ll illustrate was recently approved by the fda and then there’s gene therapy which is not yet approved but which looks pretty promising and then for the um combination therapy uh we’re combining blocking the modulated ancient bleed system with the vegf system and that was just recently approved by the fda uh and then for the dry amd there’s a delay so forgive me for these causes uh there are complement inhibitors uh one of which may be about to be approved by the fda and then there’s cell based therapy which you know sounds very sexy but i think doesn’t work too well at this point so for standard anti-vascular endothelial growth vector therapy we’ve got bevacizumab or avastin and that’s a full-length antibody the two arms of which uh and the two arms are this and this the blue and the yellow uh bind the egf there is a ranibizumab or lucentis and this is actually a fav fragment it’s just a fragment of an antibody that binds to the gif and then there’s a flipper sect uh or ilea as it’s known commercially which is a fusion protein and these are the standard therapies for what amd and they’re injected into the eye and just to give you a sense of how important these drugs are uh in 2019 13 billion dollars medicare spending uh and projected to 22 billion dollars in 2024.

This is the first or second most important medicare drug expenditure in the united states very important and how we do it uh is illustrated here first you put a sterile lid speculum to keep the eyelids open and you put in topical anesthesia uh then you sterilize the ocular surface with uh povidone iodine and then you inject the material using a very thin lean needle going into the pars minus it’s going to damage the wrap and uh it’s uh this looks pretty cumbersome but it’s actually amazing how well it works truly amazing uh which shows that you can’t use logic very effectively when it comes to this um to give an example uh this is a patient 63 year old man you can actually see the coronal blood vessel in the fundus photograph his vision was only mildly reduced to 2040.

and if you look at his flourishing angiogram there’s a hyper fluorescent area that if you look uh later on in the angiogram you’ll see that it increasingly fluoresces and that fluorescence means it’s i’m gonna go back a second that fluorescence means it’s leaking fluid which is course why he can’t see uh fortunately his other eye is totally normal with 20 20 vision and a normal angiogram and if you look at the oct and this will illustrate how important oct is you can see the fluid right there and you know what you’d never be able to see that never in a million years not the greatest rather person in the world could see that but with this machine anybody can see it it’s like a paul bunyan store so following standard protocol he gets the sentence injections and not surprisingly uh he does well uh he comes back to [Music] 2020.

uh but then he gets a recurrence which is very typical he comes in with a little reduction in his vision there’s a little bit of fluid he gets some more injections uh sorry for this delay uh but he comes back to 2020. and this none of what i just showed you is so remarkable though it’s good news here’s what’s remarkable but this person didn’t need any more injections at least not not since i saw him last a few months ago but here he is in 2015 with 20 20 vision you can tell now you’re all experts at reading the oct there’s no fluid he looks fine very unusual to only require that many injections um what are the limitations of therapy the first is efficacy uh let me show you what i mean by that these plots are all parts of the same thing but using different drugs their plots is visual improvement on the y-axis as a function of time on the x-axis so this is the plot for ilea which shows about nine letters of improvement every year this is the plot for lucentis which shows about nine letters of improvement every year this is the plot for avastin which shows maybe eight letters of improvement every year that sounds pretty good uh but uh if you’re patient you’d like it to be better uh it’s way better than the natural history the the second problem uh with the disease with the treatments is illustrated in this graph which is again applied a visual acuity uh change on the y-axis as a function of time in the excess so if you start out at baseline the patients have about 20 50 vision and by two years later they’ve got 20 70 of it excuse me 20 40 maybe even 20 30 vision which is pretty good you can you can do quite a bit with 20 30 vision but by five years later uh they’re actually worse than when they present and you know what were they going through during this time well they were getting a lot of injections 15 injections and this is in the context of a randomized clinical trial so you’re looking at just about the best results you’re ever going to see when you look at this and my message to you is that most patients require many injections over many years to preserve their vision and that is that raises the issue of durability how long does each injection last why am i saying that’s important well that’s illustrated by some data from europe and again here we’re looking at visual acuity change on the y-axis as a function of time it doesn’t matter which country you look at you could look at the uk let’s look at uk uh netherlands uh germany or rather france germany italy uh right off the bat what you notice is that even at day 60 their visual improvement isn’t as good as what’s observed in the clinical studies it ranges from two to six letters why uh if you look at it two years it’s even more pathetic for all the countries uk netherlands france germany italy is really pathetic and i’m italian so i’m saying that with some degree of uh shame well here’s the answer sorry about the way this works look at how many injections the patients got they got only a fraction of the number of objections that they needed and is it because they’re lazy is it because they’re stupid is the cuts report no the logistics of getting injections is not true especially if you’re blind how do you get to the doctor’s office so the durability issue is really a big deal and um that’s why this was invented it’s called the port delivery system uh it otherwise is commercially known as suspendable and it’s just been approved by the fda uh the delivery system shown in that circle it’s essentially a a flange device that you stick in the eye that’s got a reservoir of material that’s like a business and here you can see it inside somebody’s eye and you can see the external view of it from the conjunctival surface and when the port needs to be refilled you just stick the needle into that uh external face and that’s basically how it works how well does it work well uh it turns out sorry uh that about 98 of the patients did remove injection every more more than every six months which is a great improvement over current durability in fact if you look at the earlier phase 2 study which was a pretty large study 60 of the patients could go for 12 months with just one injection so this is really this sounds like magic right but it’s not magic uh first of all you have to go to the operating room to get it um secondly uh there’s a higher incidence of complications with this system compared to regular interventional injections there’s a three-fold higher rate of infection in the eye which is called endothelius uh and there are some complications that really just don’t happen with the injections like literal hemorrhage or implant dislocation or conjunctival erosion and of course vital detachment pretty much never happens with these injections but it does happen with this flange do patients like it yes they like it but it’s early days and where this is going to fit in is not clear i’m sure it’ll be useful for some patients but i doubt that it will be the standard thing for most patients then there’s combination therapy so just to remind you um how this works angiopletune 1 is a cytokine that binds to a receptor called the type ii receptor and by doing that it creates a mature stable vasculature but under conditions of hypoxia an angiogenic switch gets turned and all of a sudden we start making a molecule called ancient gluten two which is a competitive inhibitor of type ii and as a result angioplatin too causes the vessels to become immature and as you already know vascular endothelial growth factor is produced in settings of hypoxia and that stimulates uncontrolled and immature blood vessel growth and so that’s how you get this mess of corollovascularization so what’s the therapeutic idea the therapeutic idea is to block vegf and h2 and in so doing to create a stable mature blood vessel so in other words we leverage the body’s response we let the body make the abnormal blood vessels but then we go in and make it become mature that’s the idea and um there here’s the molecule that allegedly can do this for us it’s farisa map or abysmal was just approved by the fda it has one part of it that binds h2 one part of it that binds vegeta and one part of it which is the fc component that’s modified to make sure it stays inside the eye and doesn’t elicit an inflammatory response and you can see that um in terms of the durability about 45 of the patients need an injection no more than every four months in fact this study wasn’t designed to see if you could go beyond that so some fractions patients almost certainly would have needed an injection even less frequently about a third of the patients see the injection every three months and about a fifth every uh two months but eighty percent of the people getting injections every three to four months is a real movement in the right direction and this stuff is injected into the eye the real granddaddy of durability is gene therapy and the way that would work is that you take a virus like the agony-associated virus type k and you eat the capsule which is the part of the virus that delivers its dna into the into the target itself well you put in the dna that’s therapeutic and that would be a gene that codes for uh a vegf blocker and then you inject this construct either into the subreddit space or into the supraportal space now and the idea is to infect the retina now if you inject this stuff into the subreddit space you’re bringing the patient the operating room in my opinion that’s a non-starter but if you inject it into the super corel space you can do that in the office and that and that could work uh and this you know when when your body’s making the anti digest protein that’s that’s sustainable you know you don’t need multiple injections now this is in an early phase of development but the early data are showing what you would expect so if you look at the control group remember these people are already getting antibiotic injections so we’re not expecting the output here to be better vision we’re expecting the output to be reduced injection frequency so if you look at the people who are the control group who are getting monthly anti-vegf injections their vision which is on the y-axis is stable over time which is on the x-axis but they take seven injections to do that whereas the people that get gene therapy and there were two different doses they get that with just one injection so this could really attack the durability problem it’s too soon to say what the long-term effects will be there in terms of geographic atrophy um the i haven’t explained this but i’m going to explain it typically geographic atrophy does not start in the photo it starts out cytophobia and then over time it gradually wraps its way around the fovea and then involves the phobia and as it does that the vision goes down in this process from the start of extracurricular attributes takes on average about two and a half years well what are we going to do about that uh when you think about designing a therapy for this when you want to do the therapy is when the atrophy has not yet involved the phobia if you wait for the advanced stages of the disease you’re not going to you’re not going to preserve vision because the photoreceptors are already dead now why uh why this might work is the following and this is a slide i just added so forgive me if this seems very boring to you but i thought some of you might find it interesting so it turns out that complement factor 5a binds to a receptor on the cell and that initiates a process that’s known as the other signal priming and that leads to the expression of a molecule called nf cavity which changes dna expression uh so that it starts to produce 10 rp3 and interleukin uh one beta and 18.

and if there’s a second signal and it could be uh mitochondrial damage from oxidative damage it could be factor c3a binding to a surface receptor these solubilized materials actually become assembled and that creates signal number two which drives the assembly of these nrlp3 caspase and asc into what’s known as the inflammasome it’s actually the nrlp3 and final cell and this thing this macromolecular complex activates an enzyme that cleaves these interleukins and creates a very bad inflammatory response called pyroptosis which kills the cells and that is why we use complement inhibitors to stop georeactive atrophy i’ve shown you from genetics from laboratory studies that i haven’t shown you and from post-mortem histology the complement’s important in developing amd and uh you also know from what i’ve said that activation complement leads to the formation of c3an33b c5a and c5b and now you know in some detail that c3a and c5a activate the inflammasome which causes death and c5b creates that pore which causes the cells to die uh and that’s why we’re looking at c3 and c5 inhibitors to treat geographic atrophy and one of them is called avastin catheter it’s an rna molecule it’s injected into the eye and here you can see the results if you look on the y-axis at the size of geographic atrophy as a function of time on the x-axis this the solid line shows the rate of growth right that’s the first derivative of the treated patients versus the untreated patients because it’s the dotted line it’s a 27 production uh which is very significant that’s from the phase two study this is a different molecule of blocks c3 it’s called pexetic helpline it produces pretty similar reduction in the rate of growth of atrophy pecs had a club plan right now is before the fda for uh treating the chamber ethic atrophy i suspect it will be approved there’s another thing that happens in amd that i haven’t mentioned i just want to touch on which is the accumulation of amyloid olive oils as you all probably know amyloid is a component of alzheimer’s disease but it’s also a component of amd and amyloid algamers which are shown here and it turns out uh and if you and you can stain uh substances that drive the formation of these oligomers in an animal model of macular degeneration outside the degeneration there are none of these things inside there’s a ton of them all labeled red well you can block the formation of these things so the class of reverse transcriptase inhibitors called communities you probably have heard of reverse transcriptase as a treatment for aids but it turns out you can have these molecules that are not retrovirally active but that do block this phenomenon so this is another treatment in development and i don’t want to close without mentioning cell-based therapy nicely to tell you to be cautious of it this is a an experiment that was done uh very very carefully by dr steve schwartz at ucla using the suspension of stem cell-derived rpe cells in a patient geographic atrophy that black circle shows the planned area of the transplant and the red circle at three months uh shows you where the transplant was done you can recognize some cuts of pigment itself and there’s the pigment itself at six months unfortunately the visual improvement in these patients was normal the survival of the rpe cells and the area of atrophy was available but there’s a different way to transplant the cells and that’s using a scaffold and this work was done by dr mark henley at usc with his colleagues at caltech they used a substance called paralyncy which is biocompatible they and nano engineered it so that it’s a mesh with the thickest part being six microns thick and the thinnest part uh being three mic 0.3 microns thick and these 0.

3 micron thick areas were conceived as diffusion zones uh to allow nutrients to exchange between the uh choreocapillaris and the retina and they comprise about 58 of the surface area of the scapula you can see one of these rpe covered scaffolds in panel and if you look under high magnification you can see that these cells are cuboidal and they’re pigmented and here you see a picture of a patient with geographic atrophy uh before treatment they could see seven letters after treatment the scaffolds in that right under that area they see 24 letters this is a great result it’s not typical it’s this is still a thing early in development one idea which is a little bit uh not surprising to you based on what i’ve said is maybe maybe the thing we should be doing is growing blood vessels for patients with amt but the thing is to grow them so that they’re mature and that’s a whole different idea about how to do treatment and one that i’m not going to talk about at all but one that’s probably obvious to you based on what i’ve said um so how do we approach the patient just just takes a minute and naturally we want to know if they smoke why is that because of all the reversible risk factors the only one that really matters is your smoking history if you if you smoke increase your risk of amd by factor two if you stop smoking your wrist goes down now there are some medications that probably wouldn’t be great to be using if you have jerusalem for example plaquemine if you have rheumatoid arthritis or systemic lupus erythematosus and if we could we try to get you off that medicine the family history might be relevant because if you’ve got an early onset amd family history you might want to start vitamin neural replacement earlier than normal and of course we fully examine the eye but the real bottom line here is the test and most important test is the oct occasionally prefers some people advocate genetic testing i don’t uh the reason they advocate it is they think that it actually increases your risk for progression depending on what your complement mutations are that’s a very controversial position there might be some additional tests that i haven’t mentioned if there’s some uncertainty about the diagnosis the treatments i’ve gone through the only one i haven’t told you about is a vitamin mineral replacement i just want to mention it briefly first of all it doesn’t do any good if you have early amd it only seems to be beneficial if you have immediate amd you’re only your doctor is going to be able to tell you if you have early we like it because it reduces the risk of artificial intelligence about 19 during five-year period of follow-up but it doesn’t reduce your risk of developing atrophy it only reduces your risk of developing career investorization uh the last point about cell therapy that i want to mention that i haven’t mentioned is the real promise of it in my opinion is not site restoration it’s not site preparation it’s like restoration and that’s a a few years old anyway sorry for going a little bit but i do appreciate the privilege of being here and speaking to you and i thank you for your attention i guess i’m just supposed to handle the q a here and there are people online if you raise your hands with the people in the room who want to ask a question if you come up here because you’re going to have to ask the question here so that everybody can hear it so come on up if you want thank you an extremely impressive presentation um i’m here because my wife has the onset of macular degeneration and what she’s been told at the moment is the only thing that they can do for her is persivision vitamins but that things are coming and it won’t be long we may have some better options you went through a whole bunch of options but i don’t know which ones are are available are imminent and i guess that’s the question what what can she expect as her degeneration has been very slow but it’s beginning to i think get worse thank you very much for what you’ve done and if i able to get it i want you to be my doctor i’ll tell you what it doesn’t matter who your doctor is it’s the medicine it works the it’s hard to give advice regarding your life that’s precise but my intuition is that she’s getting worse otherwise she wouldn’t be asking what else could be done and generally um the way people get worse is one of two ways they get atrophy or they get the abnormal blood vessels i’m guessing that she’s got the atrophy because there’s already an established therapy for the red blood vessels and the way you phrase what the doctor said he wouldn’t have said it or she wouldn’t have said it that way so what’s coming down the pipe for people that are getting progressive atrophy is the compliment inhibitors and the the thing i didn’t go into for a lack of time is that you know when phase three studies are done there the the fda is you know the fda gets a bad wrap but it’s an incredibly good organization it’s remarkably good considering how underfunded it is and so they suggest things and one of the things they suggest is two clinical trials so whenever you’re doing a registration clinical trial you’re going to run two clinical trials simultaneously one of the clinical trials for the peg set coconut gave a positive result just like the phase two study did but what they all typically do and this has happened before this isn’t like the first time it happens they combine the data from both studies and see if the results are still significant and they were and that makes me think that the fda is likely to improve it’s just a speculation that they’re likely to approve the peg particularly because there’s no other therapy available uh for the um advanced like the foreign problem well the deputy has had it before them for a few months now so i i would be surprised if we don’t know by christmas uh whether they’re gonna prove it or not we have a question online alejo uh dr zarman thank you for a awesomely informative talk the medical profession has created artificial limbs like arms and legs that can be attached to the human body and controlled by nerve impulses do you think in the not too distant future is there any hope of similarly creating artificial eyes to replace diseased eyes you know believe it or not i was on a dod panel uh the short answer is not in my lifetime but i was on a dod panel where someone proposed exactly that and um and it wasn’t crazy there are a couple of problems that are really big and that doesn’t mean they’re unsolvable it’s just they’re big one of them is vascular anastomosis which you don’t need to know much anatomy to realize that’s a big big deal that’s actually the most solvable the hardest problem is the optic nerve there are about 1.1 million axons comprising the optic nerve and you’ve got a and it’s worse than that it’s that those axons all go to different places and how do they get to the right place it’s through a process it’s sort of like how did someone get into mit i mean a lot of people that applied to mit how did they get in well that sort of selection process is what determines where those accesses are and you’ve got to get that right a lot uh in order to achieve that but there’s a there’s a there are some early attempts to do what you’re saying and i didn’t mention them because they weren’t relevant to this disease but for example markham mayan uh developed a uh electrical prosthesis uh the purpose of which is to replace the photoreceptors and others have two um and the the problem uh and the reason that can work is that while the photoreceptors die the rest of the retina uh isn’t is more or less intact but the thing we have to realize is the retina is not like a circuit board okay if you if you take out uh you know the diode of the circuit board and you put in another diode you’re good that’s not the record when you take out a cell from the retina it rewires itself because it always wants to hear the music think of it that way so you’ve got to manage the rewiring process when you take that approach to site restoration but just to show you how cool the things coming down the pike are another thing you could do would be to take a cell that’s not light sensing and infect it with molecules that are white sensitive ion channels and turn them into the photoreceptors and that’s been done it’s been done and published at the level of the gangnam and it’s been done and published even better at the level of bipolar cells where the image processing tends to begin so that’s a very clever way of bending mother nature’s will if you will but the most brilliant way is to work with mother nature and that is to regenerate and that actually happens in uh salamanders it happens in zebrafish and as you can imagine that fact hasn’t escaped the attention of the scientific community and so it turned a turn and it turns out that under certain conditions you can take uh mueller cells which are one of the glial cells and given the right set of circumstances you can induce them to differentiate into ganglion cells which could be a treatment for obama or to photoreceptors which could be a treatment for number diseases among which is age-related and accurate generation that that most subtle that’s kind of closest to the creator level of manipulating biology is something that is in full force right now and i will not be surprised if assuming i have a normal lifespan if that’s actually something that happens in medicine over the next 30 years thank you are there any other questions in the room are there any other questions online yeah bill bill yes um thank you very much a fascinating talk my wife’s father went blind with amd does that increase her her chances of getting it and and how does she and yeah can can she just be tested for andy it um it probably does increase her risk of developing as she gets older but we need to know a little bit more about her dad for example did he smoke a lot yes yeah so you see that so you can you know it’s like anything else you can have like i think i have abd but i figured out through a miracle you know how to deal with it um so you can inherit something and do fine with it uh so he she may have inherited that tendency but if she doesn’t smoke maybe maybe she won’t get anything the answer to your second question is you have to undergo an eye a dilated funny system preferably by probably a general ophthalmologist will be fine but a retina specialist if you really want to be sure you’re nailing it down okay thanks very much are there any other questions online herb waddell all right yes hi um somewhere along the line i got the notion that macular degeneration develops relatively young now i’m 94.

So that means below 90. and then if you read age uh your chances of suffering from killer degeneration decline is that so or is that just it’s a wishful thought on my part it’s it’s a wishful thought but you can keep having the um so the problem is the phrase macular degeneration which is a very imprecise phrase the diseases the macula as you now know is just a location it’s not a disease and but people use the phrase macular degeneration to refer to a disease and usually the disease to which they’re referring is age-related macular degeneration but the most common cause of macular degeneration in children is stargardt disease totally different disease okay so um it could be that you got the idea that it happens early because you have knew or know someone who had one of those childhood macular dystrophies and they got that disease early um in terms of your risk of getting it if you don’t have it now the probability of you getting it is it’s as close to zero as you can calculate a probability of biology thank you [Music] roger burns one final question yes uh doctor thank you for uh scheduling your talk on the same day that i’m going for a shot at the two o’clock appointment today for my six uh sixth eye injection um i do take the preservation and uh you mentioned something about uh taking i guess additional vitamins early on my wife is an advocate advocate of the nutrients and she asked me to ask you about your opinion of lutein she wants me to take 40 milligrams a day i did ask my uh micro doctor about that and he said well if it makes her happy do it so what what’s your thought on that and one more question what are the odds of this going into my other eye uh it’s about the answer to the second question first it’s at least 50 during the next five years i would say depending on what your actual involved eye looks like now the risk could be even higher actually um but that’s okay you’ve got effective therapy and you know you’re probably going to show up on time for all your appointments and that makes a big difference believe it or not uh as far as your wife is concerned so this is a a very common i if i may call it a problem it really is a problem so people think um that if one milligram is good then 10 milligrams is twice it’s 10 times as good you know and that is not how biology works at all and i can and i’m not i’m not talking philosophy and i’m talking data so if we look at growth factors they typically have a bell-shaped curve in terms of their effects so you’ve got to hit the sweet spot and i’ll give you a very simple example if you have a vitamin a deficiency you will go blind if you take too much vitamin a you will go blind so vitamin a deficiency in the third world arctic explorers uh with the vitamin a accessed by eating polar bear livers all documented so the way to be in my opinion when you’re talking about medicine is to be imperial and the only empirical data that i think are the highest level of integrity uh clinically are the phase three of the trial data and the phase three clinical trial data with the k rex 2 supplement if you look at the bottom i will show you that it does have would more ludian be better we could talk about it but that’s like talking about urgency and completeness or something it gets into philosophy it’s not meant and the and i could give you many examples of uh i’ll give you one example the administration of oxygen uh to premature babies uh was really went big in the 40s and it saved a lot of lives and around that time there was a big incidence of oneness in these children and my one of my teachers dr arnold pass concluded that it was an oxygen that was causing avoidance so he proposed a study where he was going to restrict the oxygen exposure to some of the children and not the others he didn’t just get his grand proposal rejected uh right now he would be in the new york times his brother was a successful businessman and it turned out that he was right the oxygen exposures will cause so you see thinking is not the same as knowing right and so your wife thinks that 40 is good but that’s not the same as knowing that it’s good now there’s another problem which is that there are data that show that looting and zeaxanthin supplementation improve visual acuity and visual contrast sensitivity in older people that’s not the same as talking about treating age-related macular degeneration those are two different problems but you can see how easily people would get those two things well thank you uh appreciate your time sure well dr marco zurban rather we have two ways of saying thank you one is we’d like to present you with a certificate from the old guard of our appreciation uh you will notice on it there is an orchid and the orchid in 1930 when this society was founded was one of the orchid capitals in the united states and so we use that as our symbol the second way we have a saying thank you is a standing ovation [Applause]

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