An Eye on Education | Introduction to Gene Therapy
welcome to another eye on the education webinar i'm ben shaberman senior director of scientific outreach at the foundation fighting blindness and pleased to provide you with this introduction to gene therapy i'll be giving you an overview of what gene therapy is and also um letting you know about how gene therapy can use to actually in multiple ways to address retinal degenerative diseases so before i talk about what gene therapy is give you a definition for gene therapy i wanted to provide an overview of the different ways gene therapy can be used to address retinal degenerations the first way replace gene replacement or gene augmentation is the way we often think of gene therapy being used replacing the bad gene the mutated gene with a good gene and if you look at the clinical development space right now there are a lot of gene replacement gene augmentation therapies gene therapies in um in development now a gene replacement therapy isn't going to be right for a lot of people perhaps some people will not have their mutated gene identified there won't be a gene replacement therapy for the near 300 genes that have been identified as being associated with retinal diseases so yes gene replacement is a great approach but some of these other approaches may be more applicable to certain patients so the second approach i wanted to mention we call neural protection this is a gene independent approach so it's designed to work independent of the mutated gene causing the retinal disease and with neural protection the gene therapy is leading to to the production of a protein or proteins that help keep the retina healthy that help preserve rods and cones to thereby preserve vision again this is designed to work independent of the mutated gene uh the third approach that we'll talk about is designed to inhibit what i call a damaging pathway so retinal degeneration such as amd lead to cell loss for underlying causes let's say the buildup of druzen or the buildup of leaky blood vessels for instance in amd and gene therapy can be used to address these various damaging pathways and we'll talk about those more specifically and again targeting these pathways is usually gene independent we're not actually trying to uh address a specific mutated gene and then the fourth approach we'll discuss is called optogenetics and that's a pretty exciting albeit new approach where hopefully we can restore vision to people who have lost all their rods and cones all their photoreceptors regardless of the mutated gene that's causing their their disease and we do this by harnessing other cells in the retina provision so as we think about the retinal gene therapy space i'm not going to actually talk about specific trials or not that many but on this slide i wanted to provide a sense of how exciting this gene therapy field is right now from a commercial standpoint so this slide has logos for 16 different companies that are developing gene therapies right now in our space there's biogen novartis agtc janssen um iveric bio gensite and the list goes on and on and this is not actually a complete list these are the companies that have therapies that are for the most part further along in clinical development but it just again illustrates how much activity is in this space and as i've indicated this will continue to grow so stay tuned um for updates on specific projects you can learn about those at our website fightingblindness.org we regularly report on new clinical trials and advancements in clinical trials so that's a great place again our website to stay tuned to activity in this field so as we think about gene therapies i wanted to give you a brief review of what a gene is and how it functions and i think the easiest way to think about a gene is to think of it as a recipe for producing proteins now every cell in our body has a complete set of genes that's about 20 000 genes in each cell and again as recipes our cells read our genes to make proteins and it's really the proteins that are essential to the well-being function and health of our cells including the cells in the retina so when there's a mistake in a gene a mutation two things can happen at least in simple terms not enough protein is made or the wrong protein is made and in both cases that can lead to vision loss and loss of retinal cells so our genes as indicated on on this by this image on the left are comprised of code or letters that that make up these recipes and these letters are represented um as a t c and g and actually we have six billion pieces of genetic information in each of our cells that's what makes up our genetic profile and comprises these 20 000 genes so there's a lot of genet genetic information in every cell in our bodies so again proteins are what are really critical to the health and function of our cells on the left here this collection of strings and coils is actually an image of an rpe 65 protein rpe 65 is just one gene involved in um vision in the retina it actually processes and more specifically recycles vitamin a metabolites in the retina we need vitamin a for our retinas to be light sensitive and to give us vision and rpe 65 plays an important role in that and again the protein is what's really important to the health and the function of the cell so when we think of gene therapy a big aspect of it is getting the therapeutic gene to the retinal cells and the most common way that that's being done especially in clinical trials right now is through human engineered viruses and the most commonly used virus is an adeno-associated virus and this image on the right here this knobby multicolored ball is actually a viral container that's used to deliver a gene let's say in our case to a retinal cell and when we think about these viral delivery systems i think an easy way um to think about them is as these vast container systems so when a viral therapy is delivered to the retina there are literally billions and billions of these containers that are delivered into the retina into the cells and each of these containers carries the therapeutic gene of interest whether it's for replacing a gene or delivering a gene to make a beneficial protein these human engineered viruses are safe we the uh natural version of these viruses are common in our environment many humans are exposed to them and have no reaction so um that's one of the big reasons that adeno associated viruses have been chosen as therapeutic delivery systems because they are safe and they do a reasonably good job of penetrating retinal cells to deliver their genetic cargo so on the left side of this slide i have a diagram of a sub-retinal injection and that's the most common way that gene therapies are actually delivered to the retina right now so what is depicted in this diagram is a needle injecting a tiny drop of fluid underneath the retina and in that drop of fluid are the billions of viral containers that i was talking about in the previous slide and over time when this liquid after this liquid is injected underneath the retina it gets absorbed into the retinal cells now sub retinal injections aren't the only way to deliver a gene therapy they're the most common way at this juncture but therapy developers are also um working with intravitreal injections which are injections into the vitreous in the middle of the eye and they're also uh learning how to use injections underneath the sclera to deliver gene therapies right now sub-retinal is the most popular because it gets the therapy closest to the photoreceptors but it is a relatively invasive procedure it's a common procedure but um it is putting a needle in through the retina and injecting this liquid which lifts the retina up a little bit and and that's um an invasive process for what's already a fragile piece of tissue and even more fragile if it's affected by a retinal disease on the right side of this slide i have a cartoon of one of those viral containers getting into or penetrating a retinal cell to deliver that therapeutic cargo that gene so there are dozens of gene therapies now in clinical trials we don't have time to go through those but i wanted to highlight luxterna which is the first fda approved gene therapy for the i or an inherited condition it was approved by the fda in december 2007 and luxterna is designed for people who have mutations in the gene rpe 65 mutations in that gene lead to labor congenital amarosis one form of that disease and they can also cause a form of rp what's been exciting about this gene therapy is that in clinical trials and also in commercial use it's restored a significant vision to children and young adults who were virtually blind these kids after receiving a treatment were able to put away their canes see the faces of their parents and loved ones for the first time some could even see stars in the sky or fireflies and what's perhaps most important about luxterna not to discount those vision improvements is it provided affirmation to companies and researchers the gene therapy was in fact an effective and commercially viable approach to treating retinal diseases so the success of luxterna over the past 10 to 12 years has really opened the door to developing other gene therapies be they replacement therapies or other approaches to treating retinal degenerations so again this is gene replacement there are many other gene replacement trials underway for x-linked rp choroid aremia other forms of rp and we're going to see more and more of those so stay tuned to a lot of activity and gene replacement but as i mentioned in my opening slide there are other approaches for using gene therapy and neural protection is a promising approach because again it's designed to work independent of the mutated gene and the basic idea behind neural protection is the gene that's delivered to the retina leads to the production of proteins that keep retinal cells healthy and one example of that is a gene therapy that leads to the production of a protein that keeps cones alive that preserves cones and this one approach developed by the institute de la vision in france produces a protein called rod derived cone viability factor and what those researchers discovered is that rods produce and secrete a protein that keeps cones alive there's a symbiotic relationship between rods and cones and people with rp often it's rods that degenerate first but because rods are important to survival of cones when the rods go the cones are lost so the researchers at institut de la vision developed a gene therapy what would hopefully be a one-time injection of this gene to produce this cone-saving protein and they've actually spun off a company called sparing vision which is working toward a clinical trial this approach at the moment is applicable to people with rp and usher syndrome and related conditions and again it's really targeting survival of cones and as many of us know cones are really the most important photoreceptor because they give us the ability to read and recognize faces they enable us to see in lighted settings they give us central vision and color perception so they're the the retinal cells that are most important to our activities of daily living now moving on to that third approach that i mentioned targeting a damaging pathway and there are gene therapies now in clinical trials to both to address both dry age-related macular degeneration and wet amd and before i talk about those let's remember that amd is a little different from the inherited conditions because there are many factors that can lead to the development of amd smoking is a big risk factor it can increase risk by uh at least three or four times even more for some patients unfortunately aging is a big risk factor the older we get the greater our risk from a and d other lifestyle factors like diet and sun exposure have been linked to amd risk and there are genetic factors that can increase or even decrease our risk of amd but what researchers have discovered is that our immune system our innate immune system more specifically the complement system uh the overactivity of the complement system can cause damage to the retina it can cause loss of retinal cells rpe cells and photoreceptors and so what researchers are trying to do is target that complement system to to slow it down to inhibit it to minimize the damage that's caused by amd and they're doing that now in clinical trials at least that's the hope that they will do that through a gene therapy that produces a protein to um inhibit the complement system and there are a few clinical trials underway right now for gene therapies to do that they're targeting people with advanced dry amd which we often refer to as geographic atrophy or ga so that's for the dry form of amd uh as many of us know the dry sometimes converts to the wet form of amd and the wet form is characterized by the growth of these leaky blood vessels underneath the retina that cause ultimately the loss of photoreceptors wet amd tends to be a more a a quicker condition there's a quicker onset and it can cause significant vision loss more quickly than in dry amd not to say the dry amd can't cause significant vision loss as well it's just slower now as many of us know there are treatments that are fda approved currently for wet amd um lucenus ilea bao vue these are all injections into the eye to mop up and inhibit these leaky blood vessels the problem or the the inconvenience i should say with these treatments is they have to be injected on a regular basis for the lifetime of the patient so the patient at least monthly or every two or three months needs to go back to the eye doctor to get these injections that's that's not convenient so researchers have developed gene therapies that are one-time injections that produce proteins that are similar to those in lucenas and ilea to inhibit the growth of leaky blood vessels and the hope is with the gene therapy is you just get one injection and that would last for many years so these gene therapies are designed to reduce the burden of these other therapies that require regular injections and again there are gene therapies in clinical trials some are showing promise encouraging results so stay tuned as those clinical trials move forward and then finally i wanted to talk about that final fourth approach called optogenetics and on the right side of this slide i have an image it's a side view of the retina and toward the top of this image you can see potentially you can see the photoreceptors those long cells that make vision possible the rods and cones and in this uh image i have this ominous black x going through the photo receptors and that's to signify someone who's lost all their photoreceptors to a retinal disease like rp or amd and by definition if you've lost all your rods and cones you've lost all your vision because again it's the rods and cones that make vision possible now all these other approaches gene replacement neural protection targeting a damaging pathway those aren't going to work because you have no photoreceptors left to save or protect but some very clever researchers in looking at the retinas of people with advanced vision loss saw that other cells in the retina survive after photoreceptors are gone one of these cell types are are called um ganglion cells and toward the bottom of this image i have an oval circling those ganglion cells and what these clever researchers have done in lab studies is they've delivered a gene that expresses a light-sensitive protein to enable these ganglion cells to work quote-unquote something like photoreceptors so in essence this gene therapy is designed to bestow light sensitivity to ganglion cells or perhaps other cells in the retina that survive because ganglion cells normally are aren't light sensitive so the hope is by bestowing light sensitivity to these ganglion cells we can restore some vision to patients that have lost all their vision lost all their rods and cones to a retinal disease so a nice aspect of this approach is it's designed for people with the most advanced division laws who have lost all their vision and it's also designed to work independent of the mutated gene causing the disease now there are a few clinical trials underway for this approach um at this point we haven't had um reports of efficacy but stay tuned as these approaches develop we have even more sophisticated optogenetic approaches that are moving through lab studies and will also hopefully move into clinical trials so this is a new field we're still learning but there's a lot of promise as these technologies advance and evolve so to finish off our discussion of gene therapy i just wanted to talk about some opportunities and advantages of gene therapy and also some challenges that still remain as i've indicated in some of the earlier slides one great thing about gene therapy is a single injection should last many years for many of these approaches perhaps the lifetime of the patient and again a lot of gene therapies and clinical trials have had a good track record these aav gene therapies especially so um having a good track record bodes well for the continued development of gene therapies using the aav approaches but there are other approaches that are emerging as well that may provide advantages so stay tuned one of the challenges with aavs is there's a limit to what one of those containers can hold and some genes for example the genes ush 2a and sep290 are too big for these aav containers but what some researchers are doing is they're coming up with other aav alternatives to handle these large genes one alternative is to deliver that large gene in two pieces we call this a dual vector approach another approach is to shrink the gene somewhat so it still works but it will fit in a typical aav container we call that a mini gene so these are moving toward clinical trials they're not in clinical trials yet but we do have these approaches emerging for these large genes one thing i did not talk about was the fact that in gene replacement sometimes in addition to replacing the bad gene with a good gene you have to knock down the bad gene because it's expressing a toxic harmful protein and so in those situations you need a two-step repo approach it's not just replacement you have to also again knock down that gene um this two-step approach is more commonly needed in dominant diseases so as you see gene therapies emerging for dominant conditions like for mutations and rhodopsin you'll probably see this two-step approach uh uh targeting those situations again um sub-retinal injections are working well they are a bit on the invasive side so it would be nice to come up with uh safer approaches like intravitreal or um injecting gene therapies under the sclera but of course we have to get those to work and so those are still at an earlier stage of development now one thing that i haven't addressed at all and i plan to address in a later webinar are gene editing and rna therapies and unlike gene replacement and these approaches you're not delivering an entire gene to the retina with gene editing with an approach like crispr cast nine you're going in and cutting and maybe uh you're cutting out the mutation and maybe pasting something new in so you're not replacing the gene you're editing it and with rna therapies you're doing something to the genetic messages in our cells genetic messages are called rna and sometimes researchers address the mutation in rna and one approach that's in clinical trials puts a little mask on the mutation to block it so that the cell reads the genetic information appropriately and makes the correct protein so lots of great work going on in the gene therapy space again visit fightingblindness.org to see what the latest updates and advancements are in gene therapies if you're interested in learning about about clinical trials whether it's for gene therapies or any approach clinicaltrials.gov is a great resource and we strongly encourage everybody with an inherited retinal disease to register in our patient registry myretinatracker.org
by doing so you can get on the radar screen of researchers and companies that are developing therapies and looking for participants in clinical trials so so thanks again for tuning in to this gene therapy webinar and please check out the other webinars and stay tuned for new webinars as we post them thanks again
2021-03-16 23:22
