cure for parkinson's disease?

transcript

6 it's awful slow the onset of progression 0:09 of Parkinson's disease coming can we 0:10 actually do this and I think the first 0:13 thing to recognize is what is 0:15 Parkinson's this is not a simple 0:17 disorder this is actually very complex 0:20 disorder and the view about Parkinson's Its not just a movement disorder 0:22 is it's not just a movement disorder 0:24 it's not just something that's due to 0:27 degeneration one part of the brain it's 0:29 not just to do with dopamine it's in 0:31 fact may not even be a brain disorder it 0:33 might be something uh sweeps in from the 0:35 gut it's not a static disorder and it's 0:38 actually I don't think it's a single 0:40 disease at all I think it's an 0:42 individual disease and people need to be 0:44 treated as individuals and if you 0:46 understand this you get an idea of the 0:49 magnitude of the problem we're facing 0:50 and trying to do something about the 0:52 disease process now if you look at what What weve done so far 0:55 we've done so far is we focused on this 0:58 bit of the brain and we focus on the 1:00 fact that we know that this chemical 1:02 dopamine is missing from the brain and 1:04 if we put it back then we can control 1:06 movement and we've been doing this for 1:08 60 years and we'll either give you 1:10 levodopa Sinemet matter part we'll give 1:12 you a dopamine agonist for pinroll 1:14 pramipexole we're ticketing Apple 1:16 morphine one of these drugs and what we 1:18 do is we give you these drugs they put 1:20 dopamine back into the brain one way or 1:22 another your movement comes back but 1:24 what we're not doing is we're not doing 1:26 anything about the underlying disease 1:28 process which inevitably inevitably is 1:31 going to progress so what can we do in 1:34 the future that's different well we can 1:37 do one of these three things we can do What we can do 1:39 some neuro restoration which means we 1:42 restore or reverse than your own loss 1:44 that's going on in the brain we can do 1:47 some disease modification which in fact 1:49 means we want to try and slow down the 1:51 natural progression disease or we can go 1:54 for the big one which is neuroprotection 1:56 we want to stop the onset of the disease 1:58 or we want to arrest the progression of 2:01 the disease so does that make sense 2:02 doing this doing it three different ways 2:04 okay so if that's what we want to do how 2:08 do we do it well the first thing is that 2:11 we've got lots of stuff going on it's a 2:14 really exciting time there's numerous 2:16 different approaches to trying to 2:18 achieve the objective of altering the 2:20 course of Parkinson's disease in train 2:22 at the moment you can transplant fatal 2:25 human dopamine neurons back into the 2:27 brain to put dopamine synthesis dopamine 2:30 production back 2:31 you can modify stem cells very basic 2:33 cells to become dopamine neurons put 2:35 those in the brain to put dopamine 2:37 production back we can modify viruses so 2:41 that they contain all the genes for 2:43 producing dopamine and we can put the 2:45 virus in the brain and let it infect 2:47 neurons and start to produce dopamine 2:49 again or we can give you a growth factor 2:52 a trophic factor that will stimulate 2:55 remaining dopamine neurons to grow and 2:57 to sprout and even to spread and these Oneoff treatments 3:00 are all very valuable of protists 3:02 they're all one-off treatments these are 3:04 potential in some respects cures and the 3:08 important thing is there's ongoing 3:09 clinical trials in every one of these 3:11 areas but these things are invasive you 3:15 need to have neurosurgery to have any of 3:17 these because you need to inject them 3:18 into the brain you tend to put them into 3:20 one brain area and that's okay but 3:23 Parkinson's disease affects many 3:24 different brain areas they're 3:26 irreversible once you've had them done 3:28 there's no going back to you can't take 3:30 these things back out of the brain again 3:31 so you need to be very certain they're 3:33 safe and the other problem is you put 3:36 them into a brain as Parkinson's disease 3:38 and who knows what the parkinsonian 3:41 brain will do to newly implant itself it 3:43 might will kill them off like the 3:45 previous host cells were killed off in 3:48 the first place so what else can we do 3:52 well we can take another approach we can 3:55 design new drug molecules to attack the Classical drug discovery 3:57 disease process this would be what I 3:58 would call classical drug discovery we 4:01 can take drugs from other therapeutic 4:03 areas which we think might have a good 4:05 effect in Parkinson's disease and 4:07 reposition them into Parkinson's disease 4:09 and I'll tell you something about that a 4:11 little later on we can attack the final 4:14 toxic step in nerve cell death we 4:16 couldn't try to find the key to 4:19 Parkinson's disease and stop that from 4:21 happening and all of these again very 4:24 valuable all are in ongoing clinical 4:26 trials these are easier What causes Parkinsons 4:28 to a minister because they probably 4:29 become as tablets or injection they have 4:31 a widespread effect in the brain they're 4:33 reversible because you can stop 4:35 treatment they have a better effect 4:37 because you might also some of the motor 4:38 and the non-motor symptoms of 4:40 Parkinson's disease and what you're 4:42 doing is attacking the disease process 4:44 and that's inevitably what we want to do 4:46 in the long term it's get to the root of 4:49 this disease so if you're going to do 4:52 that you have to understand what causes 4:54 Parkinson's disease there are many 4:57 different mechanisms that can probably 4:59 lead to Parkinson's disease in terms of 5:01 biochemical pathological change in the 5:04 brain some of Parkinson's disease might 5:06 be inherited some of the factors might 5:09 be environmental and there might be an 5:11 interaction between genes and the 5:13 environment but the vast majority of 5:15 Parkinson's disease to be truthful and 5:17 I'd like to tell it as it is remains 5:19 unexplained and that's one of the 5:21 difficulties we have to overcome if 5:23 we're going to do anything about this 5:25 disease and I want to emphasize 5:28 something I want to emphasize that 5:29 people have Parkinson's disease for many 5:32 different reasons you might have a rare 5:35 gene that leads directly to Parkinson's 5:37 you might have a gene that increases 5:39 your risk of Parkinson's you might have 5:41 a gene that increases your 5:42 susceptibility to something completely 5:44 different that then gives you 5:46 Parkinson's or you might just be I aging 5:48 you might have risk factors but believe Risk factors 5:51 it or not living in the country and 5:53 drinking well water increases your risk 5:55 of Parkinson's 5:56 it could be toxin exposure pesticide 5:58 exposure 5:59 it could be diet or even gut bacteria 6:01 the other thing is it comes in many 6:04 different forms this is not a single 6:06 illness with a single set of symptoms 6:08 people have in common the fact they 6:10 can't move but around that there are 6:13 different clinical presentations Symptoms 6:15 different genetic backgrounds some 6:17 people get it late some get it early 6:19 some progress slowly some progress 6:21 rapidly some have tremor some don't some 6:24 people show different responses to drugs 6:26 your other major problem in addition to 6:29 movement might be you don't sleep well 6:30 you have pain your mind doesn't work as 6:33 well you might be tired there are all 6:35 these enormous presentations and does 6:38 this give you the idea it's not a single 6:40 illness 6:41 it's something which is more complex and 6:42 the more complex it is the more 6:44 difficult it is to overcome the problem 6:47 so how we've been going about this Research 6:49 people who leave their brains to 6:51 research having post-mortem Studies on 6:54 brains from people who died with 6:56 Parkinson's disease and what we've done 6:58 is we've gone into the brain we've 7:00 looked at the damaged areas and we've 7:02 looked at the processes which might be 7:04 disrupted that lead to nerve cell death 7:08 and we found that in some people there's 7:10 too many free radicals you have 7:11 oxidative stress in other people the 7:14 ability to produce energy in cells is 7:16 impaired at the level of mitochondria in 7:19 other people you have alterations in the 7:21 handling of proteins which clog up the 7:24 cell and cause it to die but what I want 7:27 to point out again is not all these 7:29 changes occur in everybody with 7:31 Parkinson's disease 7:32 some people have perfectly normal levels 7:35 for example of free radical formation 7:37 and I'm trying to emphasize this point 7:39 again but this is not a single disease 7:41 this is complex and it has to be looked 7:44 upon on an individual basis now what 7:48 we've done without information from the 7:49 post-mortem studies is we've gone back 7:51 to the laboratory and what we've done is 7:53 we've used toxins to mimic the effects 7:56 that we've seen in post-mortem brain to 7:59 check whether interrupting various 8:01 processes for example at the level of 8:03 energy production in the mitochondria 8:05 causes dopamine neurons to die in the 8:08 brain and then what we've done is when 8:10 we found that these processes aren't 8:12 important we've looked at drugs that 8:14 block these individual biochemical Clinical trials 8:17 changes and what we've shown in the 8:18 laboratory at least is that these things 8:21 can stop dopamine cells from dying so 8:24 the next step is logically you take 8:26 these things into clinical trial in 8:28 patients with Parkinson's and this is 8:31 where at a moment we've come unstuck 8:34 because when 38 clinical trials were 8:38 reviewed a couple of years ago what we 8:40 found was nothing that had come out of 8:42 the laboratory and taken the patients 8:45 with Parkinson's disease had actually 8:47 had a significant effect on the disease 8:49 progression in these clinical studies 8:51 but notice I say what this space because 8:54 this year you might hear something 8:56 completely different now this is very 8:59 disappointing but what we have to do is 9:01 we'd have to try and understand why this 9:03 situation has occurred now it could be 9:06 the experimental studies in the 9:07 laboratory do not limit Parkinson's they 9:10 do not give you a true picture of how 9:12 nerve cells die in the brain in that 9:14 disorder that's perfectly feasible it 9:17 could be that when we've been around the 9:19 cell all we've done is shown it if you Interrupting major processes 9:22 interrupt major processes in a Cell 9:24 cells die it's like saying if I impair 9:28 your liver it's going to have an effect 9:30 on your health if I impair your heart 9:31 it's going to have an effect on your 9:33 health if I impair your nuns or your 9:34 kidneys it's going to have an effect on 9:36 your health that may lead eventually to 9:39 death and really all we've done in these 9:42 studies is we've shown cells don't like The wrong picture 9:44 their major organelles being disrupted 9:47 and so what we might have done is come 9:49 away with the wrong picture about how 9:51 Parkinson's disease occurs but I don't 9:54 think we can be completely wrong in the 9:56 laboratory I don't think we can be 9:59 completely wrong in these post mortem 10:01 studies I think there's one other factor 10:03 that we really have to think about and 10:05 that other factor is how we've looked at 10:08 these drugs in the clinic in people with 10:10 Parkinson's and what we tend to do is 10:12 take a large group of people with 10:15 relatively late stage Parkinson's 10:16 disease we give 200 of them a sugar 10:19 tablet we give 200 of them active drug 10:22 that we're looking to see if it works 10:24 and then we go away from and look at 10:28 them 12 months later and we compare the 10:30 effects of the placebo or the active 10:32 drug on the progression of Parkinson's 10:34 disease and this is where so far we've 10:37 found no statistical difference between 10:39 these groups but what if there's 10% of 10:44 people in the active drug group who have 10:46 Parkinson's for a specific reason What if 10:49 which is different to that from the 10:51 other 190 people what if those 10% of 10:55 people were getting significantly better 10:56 in the way we do the clinical studies at 10:59 the moment we would not detect these 11:01 people we would not see an effect of an 11:03 active drug and my feeling is we may 11:06 have gone wrong by grouping people 11:07 together 11:08 and saying you all have disease for the 11:10 same reason and you're all going to be 11:12 cured in the same way so what should we 11:15 do 11:15 the answer is we need to get you early 11:18 just as Alistair stead we need to get in Get you early 11:21 there and have the greatest chance of 11:22 affecting the disease we need to take we 11:25 need to take specific groups of people 11:27 for example small group of people with a 11:29 specific gene mutation divide them up 11:32 look at them for longer periods of time 11:35 and we may have a greater chance of 11:37 success we might ever pull out patients 11:39 with well-defined subtypes of symptoms 11:42 people with Parkinson's we've got 11:44 constipation and then have a good sense 11:47 of smell people with sleep problems 11:49 focus on discreet patient groups and 11:51 their withstand a much greater chance of 11:54 having a success with one of the drugs 11:56 that perhaps we've already tested what 12:01 else could we do 12:01 well first of all we can shortcut the 12:04 process if you take a new drug from the Shortcut 12:06 laboratory and you turn it into a 12:08 medicine it's going to take 15 years 12:10 probably for that process to be complete 12:13 the risk of failure during that time is 12:16 very high the cost of those 15 years is 12:19 enormous and this means pharmaceutical 12:22 companies are often unwilling to take 12:23 the risk in going into such long-term 12:27 complex and expensive areas but what if 12:30 we do something I mentioned earlier we 12:32 take drugs which are already used in 12:35 other indications and that may also be 12:38 effective in Parkinson's shorter time 12:41 less risk less cost side effects known 12:44 because they're already in man and we 12:47 can rapidly explore hypotheses and we're 12:50 doing this this is a list of drugs from 12:53 other therapeutic areas that are 12:55 currently in clinical trial for 12:57 Parkinson's we have taken anti diabetics 12:59 cholesterol-lowering drugs 13:01 antihypertensive and E Council drugs 13:03 anti-malarials alkylating for us they 13:06 have been effective in experimental 13:08 studies and we're now exploring very 13:10 rapidly whether these drugs can also be 13:13 effective in Parkinson's and this will 13:15 cut the process down from 15 years to 13:17 something like three to five years and 13:20 here's an example this was in 13:22 newspapers 'no lafayette a drug that's 13:24 used in a form of leukemia this drug has 13:27 interesting biochemical effects and it's 13:30 been moved from oncology to neurology 13:32 and in neurology v very early 13:35 preliminary open studies have shown some 13:38 very significant effects on the symptoms 13:40 of parkinson's something that we can now 13:42 develop and do better and more intense 13:46 clinical investigation one other thing 13:49 we can do if we're not going to attack 13:51 subgroups of patients with parkinson's 13:53 what we can do is look for something 13:55 that all parkinson's patients have in 13:57 common and one thing that most people 14:00 with parkinson's have in common is that 14:01 when you look in the cells that remain 14:04 in the brain you see these intracellular 14:07 inclusions which are known as Lewy 14:10 bodies and Lewy bodies are the 14:12 pathological hallmark of the disease 14:14 process in Parkinson's disease now what 14:18 we know about Lewy bodies is they are 14:20 packed with this protein alpha-synuclein 14:23 absolutely jammed packed with it and 14:25 this protein seems to be something that 14:28 sweeps through the brain as Parkinson's 14:31 disease develops and we've been very 14:33 focused on why this protein is so 14:36 prevalent and how it might be involved 14:38 in toxicity to nerve cells and what we 14:42 found is that this protein goes it's 14:45 synthesized within cells but as it is 14:49 processed it goes from being in very 14:51 small clumps to forming in very large 14:54 clumps that eventually form into Lewy 14:57 bodies but what we found is it's these 15:00 little bits in the middle here which are 15:02 much more toxic than the big bits of 15:05 protein which eventually accumulate and 15:07 what these things which are called 15:09 oligomers or proto footballs do is they 15:12 interfere with the major processes that 15:14 maintain nerve cells in a viable state 15:17 so this protein appears in various forms 15:21 to be highly toxic not only to dopamine 15:24 cells but to other nerve cells in the 15:26 brain and what we can now do and this is 15:29 ongoing because clinical trials have 15:31 started we can stop this protein 15:33 aggregating we can prevent the 15:35 nation of aggregates we can prevent the 15:37 formation of the protein we can prevent 15:39 the toxicity of the small bits and we 15:42 really need to get the grips of how to 15:45 tackle this protein and what we need to 15:48 do again is start early it is too late 15:51 when motor signs appear you need to get 15:53 in there and stop this protein sweeping 15:55 through the brain in the first place and 15:57 here's just one example of how this is 16:00 being done this is a small drug which 16:03 you can take by mouth which gets into 16:06 the brain and interferes with the 16:08 ability of alpha-synuclein to become 16:11 toxic and this drug is in clinical trial 16:14 but with a drug company called UCB and 16:17 this will be something which may be very 16:19 exciting in terms of eventually 16:21 controlling parkinsonian symptoms and 16:24 looking at the spread of disease and 16:26 progression of pathology but this is my 16:30 parting message don't expect a single 16:34 treatment to work in everybody this is a 16:37 syndrome this is not a single disease 16:40 you have different patterns of pathology 16:42 and biochemistry going on the brain you 16:45 have different symptoms there are 16:46 different subtypes of PD there is no 16:49 single cause and no single pathogenic 16:51 mechanism and what we have to do is get 16:54 over the fact that we do our clinical 16:56 trials in one way we are not going to 16:58 find a drug which fits everybody if I 17:01 told you I was going to cure cancer you 17:04 would ask me what form of cancer I was 17:05 going to cure and what subtype of cancer 17:08 I was going to attempt to cure and 17:11 Parkinson's is going to turn out to be 17:13 different and very individual to 17:16 everybody who's afflicted by this 17:17 illness so the conclusion is there's 17:21 fantastic amounts of work going on stem Conclusion 17:23 cell therapy gene therapy clinical 17:26 trials ongoing stopping the disease in 17:29 its tracks of stopping it starting in 17:31 the first place is a much more difficult 17:34 challenge modifying things like 17:36 alpha-synuclein and its accumulation 17:38 might be a significant way forward but 17:41 we must start all of this early and what 17:44 do is must concentrate on the pathology 17:47 that occurs in all parts of the brain 17:49 not just the dopamine bit if we can cure 17:52 that that's fantastic but we need to 17:54 cure holistically the brain and rid 17:56 people of this illness thank you very 17:58 much 17:59 [Applause] 18:04 [Music]