Craig Garner: "Ethical Issues in Developing Pharmacotherapies for Cognitive Impairment"

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Craig Garner: "Ethical Issues in Developing Pharmacotherapies for Cognitive Impairment"

it’s great to be here thank you Albert and you mean so today yes what I’d like to do is tell you a little bit about the forked we’re doing and its impact on how we how we as a community need to begin thinking they told issues related to treating intellectual disabilities whether it better in down syndrome than others this is an area of quite a lot of controversy particularly because traditionally intellectual disabilities in particular and Down syndrome were regarded as disorders that were not treatable and largely not one in our society and as such there has there was a move for many many years until the 60s that chill dermot visibility of lip down syndrome should be institutionalized and if possible and you could detect the disability you know or the try some the early on and children or babies that they should be awarded so the studies that we’ve been doing are actually affecting that discussion because it argues that why any psychiatric disorder that that intellectual disabilities can be treated with drugs that actually act on the core issues that are underlying brain dysfunction so what I like to do is I have like four topics i’m going to try to compact what i want to say in about 30 so then we’re going to talk about some of these issues so what I’d like to do to give you kind of a concept is what is down syndrome how does it affect the brain how do these differences in brain abnormalities cause dysfunction what are just some of the emerging strategies that are coming up online that will treat these dysfunctions and then we’ll discuss some of the ethical concerns now the prompt to you a little bit in your thinking as I go along so you can kind of be playing with some of these issues there are many others of course there’s the one related to abortion of whether we should do this but some of the others but I listed here are reply present what are the pros and cons of implementing strategies that would improve cognitive function what factors should parents take into account in making choices for kids that have disabilities because they can’t make those decisions for themselves questions of identity what does it mean to improve cognition in an intellectually disabled person should it matter if the drug changes their personality interesting question what are the implications of drug therapy for prenatal testing and decisions about termination of pregnancy an interesting question of course is what are the short and long term consequences of drugs especially their want that you have to give every day for much of the individuals life should we give them if it’s going to cause some adverse effect that you can’t see or if you eventually find out it will shorten the life of the individual 20 years did you still do it things like that okay those are just something for you to think about so let’s begin by just shutting a little bit about what is down syndrome how it’s caused and what are the current strategies that are being used to develop therapies so I’ll tell you a little more about this but it’s caused by the triplication of chromosome 21 which has about 200 to 300 GS on it it’s one of the most common disorders genetic disorders effects up one in 600 verse where the incidence is higher and others over 35 in the US alone there are about 350,000 affected individuals 500 in Europe and greater than 3 million worldwide the impairment can be mild to severe wherein if you measured by IQ which is not really very easy to do with some of the intellectual disability can be as low as 20 which is someone who is largely unable to care for themselves and sit with are deeply in a corner to individuals in their 80s and 90s that are actually able to function quite well they’re considering high functioning individuals with Down syndrome and and they often have jobs and limited work in our society now the cognitive impairment begins already

within the first year life and more than a decline represents a lack of improvement over time whereas you know a child a normal child will have just kind of exponential both in their capacity to learn and acquire language in the first few years of life and Down syndrome you kind of quickly reach a plateau where you kind of just just slowly improve make improvements over time or not at all now not all aspects of brain function are affected in individuals with Down syndrome speech and language skills particularly affected and this is primarily because of the inability of their own brains to encode short and long term memories and you can imagine that we had a great consequence if you can’t learn today what c80 means as a cat you can’t make that Association you can’t build low category you can’t real comprehension and therefore your language suffers from it unfortunately all individuals with Down syndrome by their 30s and 40s will show all the pathology of Alzheimer’s disease and if you know this is a devastating disorder where neurons are being destroyed in the brain and so in addition to whatever retirement they have they also have this impairment which is going to cause profound effects later now until about the 70s the standard of care was very very rudimentary I’m around that time through better nutrition that are better medical care and taking the children out of institution there are lots life expectancy went from 25 years of age to 45 to 60 that’s another big change for them in their lives importantly by inclusion inclusion education and socialization there was a major change in their functionality they went from being kind of not even part of our world to being amazingly integrated that was a big major change in their lives by being able to be part of society being included in high schools etc unfortunately there are no formal treatments for their their cognitive impairment this leaves the patients dependent on you know on society for years long after their parents have gone obviously if you’re having a child with Down syndrome in your 30s and 40s that they will outlive you especially now with better treatment so the economic impact alone is enormous in terms of kind of treatments that have been considered one of the earliest ones in the 60s to simply they thought this with a problem of vitamin and micronutrients especially from the work of will night Pauline and others which said okay vitamin C can cure everything there is an effort can use vitamin supplements in this patient population but eventual clinical trials through this July they aren’t important they didn’t change it and cognitively they’re also a variety of others i only talk mention a couple of them because of the connection to alzheimer’s there was a thought that the drugs that were being developed for alzheimer’s patients in particular those that were affecting the levels of cell choline which is a neurotransmitter that’s important for kind of awareness and attention that they try to variety of these drugs in these patients and they had effect at all so effectively as of about 10 years ago which is relatively recent there are no known drugs shown to be effective for improving any aspect of brain function and Down syndrome so there’s been effectively in the last 10 years a revolution in the neurosciences with the recognition that many of these disorders in autism Down syndrome you know these are actually addressable pharmacologically to actually develop therapies that can address either behavior beyond just simply let’s drive drug X Y Z which is how psychiatry was driven until the 70s where we would just experiment on you willy nilly I would say let’s just try and run X Y or Z on you and we’ll see what happens this is happening in institutions across this country and around the world extensively so a lot of drugs like we know lithium etc were used because they seem to do something in this population versus other we were experimenting on humans so this is no longer wow you’re not allowed to do this although doctors can do a lot so the strategies that moderner signs

are taking is first to say well what is wrong in in patients with any given disability leg out syndrome we largely are using animal models a variety different ones that we hope will reflect the human condition and in so doing will be able to define mechanisms and then develop rational therapies so this has been like a wave that’s passing through our community and the impact of this is huge so what is down syndrome I already mentioned that these are all the chromosomes in human and it turns out that in down syndrome chromosome 21 is found in three so ninety-five percent of all patients with Down syndrome have three copies of 21 chromosome 21 and about 5% have what we call partial try zombies where a portion of chromosome 21 will be tethered to another chromosome and propagated through the individual affected is there many facets of their brain and features so what does it mean to have an extra chromosome well you all know what chromosomes are the chromosomes are found in cells they actually are composed of DNA and DNA encode genes and these in turn encode proteins so DNA is rise to mRNA messenger RNA which then gives rise to protein right and so all of our cellular functions are defined by the proteins that we have so we contain a piece of DNA and it makes RNA we’re just representing the exons of that gene in different colors we combine them together and this then gives rise to a protein which has several different parts of domains now how genes affect who we are well clearly what kind of genes that we have affect whether we’re for example short or tall and this is really a bounce of like growth hormone will be an interesting example the protein which could do this and then if you have a certain amount of that protein you can either be all or short and the amount of those proteins really affect what you become and if you have more of those proteins for example more growth come on we can make you be part of course if you drink eat a lot of McDonald’s hamburgers you don’t need growth hormones you can also from the environment very large and my son is 64 is a good example I won’t say it’s due to hamburgers they some form on steroids in our beef okay so then you get some room is much bigger so in the case of Down syndrome what we have to face is that there are 300 of these genes which are triplicated so this is a classic gene dosage disorder it’s a disorder in which we have one extra copy of a gene or more than one this means that you have fifty percent more of that protein and it’s affecting the equilibrium which is driving you to be at some new characteristic it doesn’t necessarily mean that okay so you get new characteristics so in the case of Down syndrome one could predict that there are some of those genes that are responsible for the cranial facial features the length of the bones that they have their stature they’re there they’re largely shorter they actually have they are often overweight they eat too much they of course have all these cognitive disorders so that’s somehow all of those jeans or some sets of subsets of those jeans are actually responsible for the phenotypes that we see okay this is clear there’s a kind of simple concept to just want to make sure we’re all on the same page do you think about that so if we now kind of walk through trying to define much long I told you the one thing that’s wrong as we have all these extra genes but how do these genes play out in terms of how the brain is working and what parts of the brain are working or not working so really elegant work that’s been done by linda del and published in the early part of 2003 basically has characterized some of the main features some ways i’ve already mentioned to you Laureen is normal and very very young subjects less than six months of a but declined progressively in the first year this decline occurs an adult with a risk of early onset alzheimers making a further impact on them I’ll just drop down to what’s really intriguing is that impairment is not across all learning and men systems now we think of learning in memory the form I experiences this room and the people who are here and this talk today this is then logged into short-term memory and then during your sleep oddly enough this is a time where

the short-term memories are moved into long-term memories in your to your cortex which you can then have access on to tomorrow as a result of your sleep and the next day and years to come okay so there’s kind of two step process of that and the hippocampus is a part of the brain this is absolutely essential for short-term memory acquisition our sensory information comes in its processed by our hippocampus and this allows us to the current information and then it’s the movement of that information into the cortex which gives you your lawn chairs and these are really disrupted in this patient population of all the members of their cerebellar memory functions which are involved in movement and gate are not a pair so it’s not like all systems are affected equal I mean as I mentioned earlier these have really big effects on language speech and verbal so if we want to figure out more about what centers of the brain are doing this we can look at issues of neuropsychol psychology but we can look at anatomy and if we look at the anatomy of the brain of an individual with Down syndrome versus a healthy individual that doesn’t have three copies what we notice is that the cerebellum is much smaller you can kind of see that the whole cortical areas are actually reduced the number of Gir reduce and in fact the hippocampus which I just mentioned it’s important for memory function is smaller our further studies have looked at the anatomy if you just take a segment of the cerebral cortex each one of these dots represent an individual cell neuron or Leah that’s in the brain and you can see just by comparing an age-matched control that the number of cells are making out the cortex or lot less so this implies that there’s some deficit during brain development which is affecting cell number one of those cells migrate into the right layer so this is a parietal cortex of a newborn and you can see where all these individual neurons with their dendrites or axon sir making up layers that make up the cortex within the first year of life two years of life the total number of cells don’t change but what does change is the arborization of these cells and as I’ll show you in a second this authorization is related to the number of synaptic inputs that a self has those synaptic inputs synapses are you’ll see a second or the sea of learning and memory so how complex these harbors are tells you something about how well brain is able to learn and in down syndrome you have more of this situation than this one indicating there must be some problem with the wiring and the number of connections a very cool way to look at this is to look at one cell and here is one cell one neuron in a cat visual cortex which has been filled and you can see where the entire dendritic arbors quietiy senses this is the soma these are the dendrites which receive all information and then the axon which is a single axon which comes out and then goes it makes contact with other cells on this quite elaborate this has actually been squashed into two dimensions but in fact is like a Christmas tree is in three dimension that covers a lot of space so if you jump back and place this one cell into sorry into this cortical layer each one of these spots represents one of these really incredible dendritic trees that are woven in between each other okay now what happens is if you just focus on one end great segment and blow it up this is one dent right here you’ll see that the dendrites have these things called forms or dendritic spines on the surface of them and if you look at these thorns by electron microscopy this is one of them here you’ll see that each one of them is contacted with a presynaptic bouton from an axon from another cell okay and so this unit is called the synapse and it works by taking neurotransmitters which are black barbers or storing these vesicles they go in fuse with the membrane they release the transmitters they act on a receptor on the postsynaptic side and trigger an electrical signal that goes to the brain importantly this little unit here is what encodes every single bit of information that we take in it takes about 1 million neurons and about three synapses per connection to encode one memory trace which would be your first glimpse of the mountains showing some horizon the next memory chase would be your car driving into the campgrounds at Yosemite or Tetons etc so those memory traces add one to the next and it takes

about that many neurons and that many of these synapses to a code one bit of information ok you can interrupt me anytime so it’s important about that piece of information is is that that actual number of these spines tells you how many synaptic contacts a cell is able to make and in this particular case most cells make 20,000 synaptic contacts so we can play a very interesting working performance of experiments and Down syndrome and look to see whether these spines are forming in normal numbers over time and so this is normal development where has very few synapses to begin with it very few signs and about by one year to three years of age you can see that the number is enormous furthermore they kind of become from long and thin to being very regular in shape over time so these are hallmarks that there’s a sin asses and if you look at an individual with Down syndrome these spines are long and thin and some of them are big and their numbers are really small so these are all elements that argue that there’s a somatic defect okay so that gives you some of the background of Down syndrome that we think that there are deficits in synaptic learning that they are affecting the hippocampus and certain parts of the cortex and as though that gives us a structure to begin thinking about what we can do however as I said since the 50s we aren’t allowed to experiment on humans and you probably appreciate that but I don’t come asking for for you to give me some of your brain tissue like an experimental of course we can use fMRI and other things like that are non-invasive but those techniques don’t give me single-cell resolution they really want to tell me how the circuit is function with it so there are a variety of animal models this one here is a clas which is about one millimeter in size this is after softly both of these systems are great for genetics but almost all studies that are looking at behavior related things and jeans and trying to copy human condition both we use mice or on other roads higher animals are not almost not used although there are some that are using higher level organism but for all the studies I’m going to tell you about relate to the mouse if we wanted to create an animal model of Down syndrome in the mouse we have to consider that we want to basically create a try so me we want to be able to take the genes that are found on chromosome 21 and make three copies of them in a mouse so human chromosome 21 I told you has three hundred genes and in debt and a mouse those three hundred genes are actually play stint on 23 chromosomes enclosed walks one is about 200 genes here on chromosome 16 50 more on 10 and 50 more on chromosome 17 so if you wanted to make a try Soumik mouse you would have to take this block of genes here here and here and triplicate them now using chromosomal engineering this has been accomplished to its entirety within the last year by reaching you keep you so that mouse has been created but there have been otherwise that have been existing for some time which only take this distal end or this segment of chromosomal time this segment of chromosome 16 and triplicate stack and that’s shown here so that all the work I’ll just mentioned to you has been done with your spawn mouse and what’s really interesting is that this mouse has like eighty percent of all the phenotypes seeing in doubts in you so for example I mentioned to you about the cerebellum being smaller and in this mouse model the cerebellum of these mice a smaller the hippocampus is smaller the cortex is smaller they the same cranial-facial deficits they have the same learning deficits which are epic ample and prefrontal face so this argues on many levels that these are pretty good not perfect models they don’t have heart defects they don’t have leukemias they don’t have all the features but those must be depressed some of these other chromosomes so to explore using these animal models what’s wrong what we use is something called physiology this basically puts an electrode into a cell and listens to it and this is a selfie ur firing thought that can win Morse code okay we can listen to them and we can learn a lot about so the area of the brain that were most interested in is the hippocampus which is shown here and most of that came from the gentleman named Henry hm he was gone for many years who just passed away recently who had damage to

his hippocampus and what’s interesting is he had only long-term memories what he had learned before and he had no short-term memory he could see you and you introduced him hello Albert my name is Craig garner and Albert if he was a gem would say hi Craig and then five minutes later I walked over here and i come back and i would say hello to him again and he couldn’t remember me okay and in fact he this happened when he was 21 years of age and when he was 50 x showed Albert hm a mirror and he looked at himself here we go who is that because he had no way to store long-term members so the hippocampus is a really important part of our members so we can go into the hippocampus we can use electro physiology and we can listen to cells as we give them a stimulus and ask for their responsiveness and the result of this has told us some very interesting things about what’s wrong first of all what we’ve learned is that this synapses are able to encode information but one set of synapses which are illustrated here which actually dried inhibitory tongue are much too laughter so if we just look at the downward spikes here this represents individual synapses firing of the inhibitory type and you can see that the numbers are much increase in these brains so what this tells us is that and because of this these synapses are unable to learn so an example of learning is I give it a positive response of electrical pulse and it responds but they post synaptic responses I do this several time and then I give it a tetanus and say okay I want you to really learn something and most announces get stronger and they’ll hold that new strength for some time whereas these animals are unable to do this now the reason for this is is that that the inhibitory tone in these animal seems to be too hot and this is suppressing synaptic plasticity and thus interfering with neural circuits okay so by studying these animals we’ve learned this and in doing so we were able to actually make a prediction about what’s wrong and actually then create a strategy for treating this disability so to do that our prediction of course is there’s too much in addition and we want to use drugs that will reduce that inhibition and we developed a model that actually can test this in our animals it’s based on object recognition and children with Down syndrome cannot do this this basically I give them two objects today and tomorrow I’ll give one of those things objects again plus one new object and invariably they will not be able to remember that they saw that other object from yesterday and part of that is measured by attention so what we do when we see a new object is we spend more time exploring it ignoring the other okay and so the degree of intellectual disability correlates with your error rate so this can be actually done in these lights and this is the movies showing mice that are in four different chambers these are objects and they spend a certain amount of time going up and touching them and if it’s a novel object they’ll spend a lot more I’m with it on then another so doing this type of experiment we can actually examine whether these mites have deficits in learning so in this experiment Ford actually today training them with two different objects the next day we give them one of the same one new object and we have a measure of the index of discrimination in a normal animal will actually spend almost all this time of the new object and it turns out this mouse model spends equal time in both objects indicating that it hasn’t learned that the problem so faded fernandez a graduate student a really talented graduate student in the lab came up with this idea and what he then did was take a simple drug tempting tetris all which can be used at very very low doses to remove the gaba inhibitory tone and ask whether or not learning would be restored in this example here what we post treatment of this drug given and chocolate milk we just put a little thimble the chocolate milk in it with this little drug it’s like ten microliters they eat it today and then do our test fitting etc so what happen is that we gave it for three weeks is that you can see that the performance of these animals on pendulum tetris all this is saying this lot of time really really cruelly is that two months after they’ve had a free week regiment of this drug they are performing still as well as they are well type littermates this was really profound this was really really cool is really exciting and suggested many things it said for the first time that intellectual disabilities in down

syndrome are a caused by too much in addition and secondly that it could be treatable by giving low doses for drug so this is very cool we published this in 2007 and since then our group has founded a company to develop this drug we’ve actually done all critical preclinical studies to show it’s safe and we are entering a phase 2 clinical trial in down syndrome in this spring so March of 2012 we began our study begin evaluating this drug Oh what exactly the drove through it again it’s preventing the inhibitor it basically reduces very very slightly the amount of inhibition and what happens over time is that if you give it once a day your inhibitions is excitation and emission so excitations where we’re learning in a vision if it’s too high you can never learn and normally what happens in our brain is that this is in this state and when some new information comes in addition is turned off we learn something and that inhibition comes back up and we keep that memory intact and what’s happening here is the inhibition is so high that they never learn and the idea was is if we give a little bit of this drug every day that you will slowly drive down inhibition because the excitation gets stronger and that balance will come back and equally okay so it’s it’s similar in many regards all drugs not mention just a few of them in stock is that drugs that we use in neuroscience are all acting on neurotransmitter systems we have inhibitory system like gabba gabba courses in the favorite target of rush and other major companies who make valium and drugs that inhibit or increase the activity of the GABA receptor causing you to go to sleep or sedate SSRIs are drugs that actually act on the serotonin system another transmitter and effect depression and other ADHD drugs through something similar so conceptually you realize now that we’re almost there right we’re actually at the door of being able to treat asian with Down syndrome for their intellectual disabilities and the drug that I mentioned is that playing Tetris all and it’s acting to normalization inhibition but we’re not alone since we published this paper instead this was possible many many other groups have looked at all these other systems so there is our is work done with fluoxetine also known as prozac an SSRI which can be used to normalize the number of cells that are being born in your brain notably our studies and theirs are being done in adult individuals so what that means that you can actually intervene in an adult you don’t or a young a child you don’t have to intervene at birth but there are some that you might have to do that way there are even others like vogelin which is an ADHD drug in these mice as coach with Down syndrome have ADHD so what you’re really facing in terms of developing a treatment that will remove as many of these phenotypes as possible is some cocktail of drugs that are ultimately going to be necessary