Elizabeth Berry-Kravis M.D., PhD, Professor of Pediatrics, Neurological Sciences and Biochemistry at Rush University Medical Center in Chicago, talks about a devastating genetic disease that acts like Alzheimer’s in children.
Interview conducted by Ivanhoe Broadcast News in June 2016.
I know there are several types such as Type C. Can you tell me what that is?
Dr. Berry-Kravis: Niemann-Pick Type-C (NP-C) is a disease where abnormal amounts of cholesterol and other fat-containing molecules are stored in the lysosomes in cells. The lysosome is an organelle (a little organ) in a cell that is responsible for breaking down and recycling molecules from the cell. It is like the recycling center of the cell. Niemann-Pick Type C is one of the broad category of lysosomal storage diseases. The other types of Niemann-Pick diseases are other storage diseases in which some of the material being stored in the lysosome is similar to that being stored in Niemann-Pick Type-C. Because of the similarity in the material being stored in the lysosomes these diseases originally all got called Neiman Pick. But as we learned they were different types of diseases and found the genes that cause each of them, we were able to sort them out into the different categories. For instance in Niemann-Pick Type A and B there is an enzyme involved that is different from the problem in Niemann Pick Type C. In Niemann-Pick Type C the problem is that the cholesterol which usually goes all around the body and brain, and has functions in the brain cells gets stuck in the lysosomes. Normally it has to go in to the brain cell and has to move through the lysosomes to go back to the cell and do all of its functions. In Niemann-Pick Type C one of the transport proteins that move the cholesterol through the lysosomes is mutated. Then the cholesterol gets stuck and it stays there in the lysosomes and accumulates. When the cholesterol accumulates it causes other fat molecules to accumulate nonspecifically with it in the lysosome. Also the cholesterol can’t go into the cell and do all of the things that it is supposed to do. So in Niemann-Pick Type C there may be absence of functions that cholesterol is supposed to do plus toxic functions of cholesterol building up in the cell.
Where does it accumulate?
Dr. Berry-Kravis: The lysosomes work as the recycling center of the cell. All neurons have lysosomes which is where the cholesterol gets stuck and accumulates. Then the lysosomes sort of swell up and the brain cells get packed with cholesterol.
You talked about causes, tell me about that?
Dr. Berry-Kravis: NPC-1 and NPC-2 are two genes that we know of that can cause Niemann Pick Type-C. NPC 1 is responsible for about ninety five percent of the patients that have NPC and NPC 2 is responsible for only about five percent. Both of these genes code for proteins that go into the lysosome and move the cholesterol through the lysosomes. Without those proteins being present and both functioning pretty normally the cholesterol can’t flow through the lysosomes and do what it’s supposed to do.
Are these genes from the mom’s side or the dad’s side?
Dr. Berry-Kravis: If a person just has one bad gene it doesn’t really cause disease. This is what we call a recessive disease which means that you have to inherit a bad gene from both your mother and your father so that both of your genes for the protein are mutated and then none of your protein is functional which means that you then get the disease.
Why is it called Childhood Alzheimer’s or referred to as that?
Dr. Berry-Kravis: Originally it was referred to as Childhood Alzheimer’s because some of the proteins that were accumulating in Niemann-Pick Type C were similar to the proteins that accumulate in Alzheimer’s disease. It’s also because it’s a progressive dementia or loss of cognitive ability which is similar to Alzheimer’s disease. It’s really not the same disease process as Alzheimer’s disease.
What do we start to notice when kids have this?
Dr. Berry-Kravis: This disease presents itself in highly variable ways. A patient may be found to have a big spleen or liver when they’re a baby. Sometimes there’s a big spleen when the patient is a baby and doctors never figure out what’s wrong, but the enlarged spleen never becomes a real medical problem and the patient grows up and then develops symptoms later. Other times nothing is noticed and the child seems to develop in a completely normal manner for a while until they start to develop symptoms of a neurological disease. It often begins with learning problems or difficulties in school that can be coupled with tremors of the hands so that the patient can’t manipulate objects normally. There can be balance problems, something we call ataxia where patients have difficulty maintaining their balance when they walk. There’s one very classic sign of Niemann-Pick Type C which is called vertical gaze palsy. This means that when a patient tries to look up rapidly they can’t do it so to compensate the patients tend to turn their heads up to look up. This is something that families notice early on but they don’t necessarily know what it means. This abnormality of eye movements is one of the early signs and can be there even before the balance or fine motor problems. As patients grow older they develop problems with swallowing and problems breathing in the later stages. It’s a progressive disease and there’s a progressive loss of intellectual functions to the point where the patient may have talked before but gradually loses the ability to talk or think and do really anything over time. The progression is quite variable. The patients that start to develop symptoms earlier when they’re preschoolers for instance progress more rapidly than the patients who develop symptoms when they’re older, like in their 20s. It’s possible to develop symptoms of this condition at almost any time in life. Patients can develop a very early onset infantile form or begin to show symptoms in your fifties and sixties. It just depends on the severity of the effects of the mutation in the cell and the interaction between lots of other things that could potentially make the condition milder or more severe.
It seems like because they’re completely normal, it sounds like sometimes as a child they’re pretty much the same. They hit all their milestones before the first grade then start developing learning disabilities. How often is it misdiagnosed?
Dr. Berry-Kravis: It’s misdiagnosed a lot. There’s actually a diagnostic odyssey that occurs a lot when there’s something wrong. Hayley, for instance had some learning problems in the first grade. Often families start going to psychologists to try to find out what their child’s learning disability is and how the school should best adapt to that. Then as time goes on, it’s a little more than just a mild learning problem. The patients starts to separate developmentally from their peers and starts to lose skills that he or she had before and then the family is going to neurologists to try to find out what the cause is for this loss of skills. It may take years for the disease to go from just developmental stagnation to actual regression. Sometimes it’s hard for the clinician to recognize what’s going on. Other times, signs are missed, like for instance the up gaze problem which is really characteristic of the disease may be missed or somebody who sees it may not understand what it means. The patient doesn’t receive a diagnosis for a long time and the average amount of time it takes to get a diagnosis of NP-C right now is about five or six years, which is a huge amount of time for patients to be going to doctors and having diagnostic tests without getting an answer. For instance, Hayley then developed intractable seizures and went to epilepsy doctors for quite some time. She wasn’t diagnosed until after she had deteriorated quite a bit. The older patients that present symptoms as adults are often thought to have early onset Alzheimer’s disease but they usually have other signs that people with Alzheimer’s disease don’t have- such as balance problems and the shaky hands which are not necessarily signs that you would see in Alzheimer’s disease. So there are ways of distinguishing NP-C but again if doctors are just coming up with a common diagnosis that they see a lot and not thinking about NP-C then they don’t necessarily make the diagnosis. Recently we’ve had a new route to making the diagnosis that may change some of what we know about NP-C; this is a new test called exome sequencing in which they just sequence all the protein coding genes in the body. Often when a neurologist is faced with a confusing patient that has a bunch of neurological symptoms likely to be something genetic and he or she does not know the diagnosis, rather than trying to figure out the diagnosis one test at a time, and especially if there’s nothing specific that really identifies the condition or if the up gaze palsy is not seen, the doctor can send the exome sequencing and just look at all the genes. We’re getting patients diagnosed now who had some symptoms and their neurologists didn’t really know what it was but they just sent exome sequencing and then the disease was identified by finding mutations in one of the NP-C genes. I have seen two patients in the last six months that were diagnosed because of that route of diagnosis rather than recognizing a specific clinical syndrome.
Diagnosed with Niemann-Pick?
Dr. Berry-Kravis: Yes, with Niemann-Pick Type C because the neurologists knew there was something wrong with them but they didn’t know what it was so they sent exome sequencing to try to find it. The recent availability of that test in the past few years is probably going to have a big impact on the patients who are diagnosed and the way we make that diagnosis.
How long has that been around?
Dr. Berry-Kravis: It’s been gradually becoming more used; I would say it’s been around in some form for at least five years. But it’s been used more heavily clinically in the past two or three years.
Now it’s Niemann-Pick you’re saying, it’s kind of a progression but they just know it’s going to get worse, it’s going to worse and worse.
Dr. Berry-Kravis: Right.
Tell me about this study that’s going on?
Dr. Berry-Kravis: Right now, the trajectory of NP-C is that it’s going to get worse. The rate at which it’s going to get worse is quite variable from one patient to another. For instance one patient might deteriorate over two or three years if they are a very young child when they get the disease and as for another patient, if they get the disease in their twenties they might deteriorate over twenty years. The progression is very unpredictable and exactly how much and what will deteriorate when is also unpredictable. The bottom line is the patients don’t get better; they go downhill once they have developed symptoms. The treatment that we’re using right now is something called cyclodextrin. Cyclodextrin is a circular molecule that is used to dissolve things that are not dissolvable in water. The cyclodextrin has been used for some time to make things like steroid solutions that you might infuse in an IV into a person if they came in to the hospital and had to have a steroid infusion. So cyclodextrin is a drug that’s been used in people for a long time as the “excipient” (the thing that we put in the solution to dissolve the important thing that we want to treat the patient with). There were researchers that wanted to treat the mouse with NP-C with a specific steroid drug called allopregnanolone and the molecule that is used to dissolve allopregnanolone is cyclodextrin. So when they gave the mouse the allopregnanolone, it increased the survival of the NP-C mice, but the control mice that got the solution without the allopregnanolone also had an increased survival. So it was kind of discovered by accident that the cyclodextrin in the solution was what was causing the mouse with NP-C to live longer. Subsequently, cats with NP-C were given the cyclodextrin. When they gave the cat the cyclodextrin in to the spinal fluid it extended the life of the cat a great deal. In fact the cats with NP-C start to develop symptoms at two or three months and go progressively downhill and die at about six months. The cats that got the cyclodextrin before they were affected are still alive around four years of age so that’s a huge effect on survival. The survival depends on the dose of cyclodextrin that is used. The cyclodextrin has to be given in to the spinal fluid because it doesn’t cross across the blood brain barrier. It doesn’t go from the blood into the spinal fluid and into the neurons very well; only a tiny amount of it goes in. You can use a really big dose and give that through a vein, but when doses were given that were big enough to get in to the brain to really extend survival in the cat, then the cats developed lung disease from the cyclodextrin itself, so it doesn’t seem to be a good option to give cyclodextrin in an IV to treat the brain. Some patients have spleen and liver disease so they have disease in their organs outside the brain in which case giving the cyclodextrin through an IV is a reasonable thing to do to target those organs. But to target the brain we have to give it to where the brain is. This drug started to be explored in humans as a treatment for NP-C about five years ago. Before the first trial, the NIH Phase I trial there were several individual treatment IND’s. An individual IND is when a doctor gets approval to use a drug that is not yet FDA-approved through the expanded access program (also called compassionate use) at the FDA. Johnson & Johnson agreed to provide the drug as a compassionate use drug for patients that wanted to go on it with the plan that there would be a drug development program for use of cyclodextrin in NP-C. Through this route, two families got on cyclodextrin before the NIH Phase I trial actually opened up. Then the Phase I trial at NIH opened up and enrolled fourteen patients. But not all patients could get in to that trial while it was running because there were certain inclusion and exclusion criteria. Hayley Koujaian went to screen for the trial but she was not eligible because Hayley had too many seizures and was on too many seizure medicines. Once Hayley was not eligible to go into the trial she could get treatment through an iIND or expanded access protocol. When the Koujaians were not eligible for the trial they came to me and they asked me to do one of these compassionate use protocols. This is a lot of work but I couldn’t really see myself saying “no” and so we created an expanded access protocol. I talked to the NIH and got several different protocols and worked to create what I thought would be the best protocol. I also organized collaboration so that we could collect the same kinds of measures that NIH was collecting so that if we were going to treat patients at least we would be able to know exactly what was going on with their disease course over time. In the Phase I open label trial in which everyone got treatment with cyclodextrin, it looks like the trajectory of disease was changed in those patients relative to natural history patients that never had treatment with cyclodextrin, but were just tracked along over time. On the basis of that data as well as all the animal model data and all of the biochemical data a phase 2/3 clinical trial for FDA approval of cyclodextrin for treatment of NP-C was able to be initiated. Vtesse is the company sponsoring this clinical trial. They are using a form of cyclodextrin (which can be many somewhat different preparations) called VTS-270.This is the same product as the Johnson & Johnson product that was used in the Phase I trial and the iINDs in the USA from which we have all the safety and treatment data from the patients who have already used VTS-270 previously. The trial is a sham controlled trial which means that some patients get an LP and the VTS-270 infusion and some patients get a fake LP but don’t actually get the drug but everything else happens the same as if they were going to have an LP so a needle is put in the back but not into the spinal fluid so the full LP is not done. The sham controls needed to be done to really prove that the drug works and receive FDA approval. That trial is currently enrolling patients but not everyone is eligible for that trial. Patients have to be between the age of four and twenty one and have to be at a certain stage of disease progression. The patients that get randomized to the sham treatment will get cyclodextrin in a year through an extension of the trial in which everyone gets VTS-270 treatment. If they deteriorate too much in 6 months they can go out of the sham-controlled part of trial and go into the extension where they get the VTS-270. This is a protection for the patients in the trial because of the sham part of it. For patients who are not eligible for the trial, like for instance a thirty year old patient or a two year old patient, they can still go into one of the compassionate use iINDs. Right now here at Rush we are running the Phase II III VTS trial of VTS-270 . We have eleven patients in that trial at Rush. We also have an IND for our compassionate use protocol. Our IND is for a multiple patient IND that we are using to treat six patients in right now, who are all patients that either didn’t qualify for this trial or couldn’t get in to the Phase I trial that was going on before and came into our IND then.
What this drug is doing is it kind of reversing?
Dr. Berry-Kravis: If you give the drug to the animal models, it pulls the cholesterol out of the cells. In fact if you put the drug on a tissue culture plate of cells you can see the staining of cholesterol in the cells going away. It pulls the cholesterol out of the cells in the brain and if you give it before the cells have all degenerated you can see protection where not as many of the cells in the brain die as would have if the animal was untreated. Obviously we can’t do those kinds of studies in people. Instead what we do with people is we track function and we think that once neural cells are dead they’re gone and you really can’t regenerate them so the expectation is we might be able to halt the disease or slow its progression. We don’t really know though and the ability to stop or slow the disease might be different for different people. It is likely that this drug is not the perfect treatment, that it’s not going to completely stop the disease long-term and so we will likely need other things in combination with this. But this could at least give us a period of time to develop those other things during which the patient’s progression will be stopped or slowed while other things can be developed out of basic science. With that being said there may be some neurons right when you start treatment that are kind of on the border. They’re not quite dead, they may not be functioning very well and you may be able to get back a little bit of function from those neurons that are kind of on the border. Hayley for instance was hardly talking at all; she had lost most of her language when she went onto treatment. It wasn’t that she couldn’t say words it was just that she didn’t say words. But after she went on the treatment she began to talk a lot more and she sings and she can be very talkative sometimes and she’s reading words. Some of that is knowledge from the past that she can bring to mind better, and we’re trying to figure out if she’s actually learning to read new words or if these are all just words that she already knew. But none the less she’s doing those things and she wasn’t really doing them before she came in to the trial. Before she came into our IND she was experiencing choking when she would try to swallow or eat and now she’s much better with that. In fact when we do a swallow study with dye in radiology and watch her swallowing mechanism we can see that her swallowing mechanism is better since she has been on treatment through the IND. These things correlate with the fact that clinically the family is not seeing nearly as much of the choking. Her walking has been a little more balanced and it seems like that goes up and down a little so I’m not sure she’s a huge amount better than she was, but she’s not worse which is the really important thing in NP-C. We have a very extensive battery of tests that we do because I felt that if we were going to use this investigational drug we would want to know what it’s doing. We’re doing as much as we can to define what’s happening over time. We have a battery of gait and balance measures, of measures that test fine motor function. We use swallowing studies, we use eye movement tracking and we use a battery of cognitive and language tests that measure all the areas that NP-C hits the most in terms of brain function. I can safely say that we have not seen any of those measures go significantly down in any of the three patients that we’ve now treated for over two years. Do I know that those measures would have gone down in those two years? I don’t a hundred percent know that because one of the patients is not very affected and who knows when there would have been a start to progression. One of the patients was mildly-moderately affected and has had a lot of balance and tremor issues. I would have thought she would have shown some worsening and she hasn’t really shown any worsening on all these comprehensive tests that we’re doing to really monitor every little bit of function and detail. In fact some of the tests have gotten better. The IQ scores of two of our patients have drifted up a little bit and sometimes you wonder whether if it’s enough to be significant but it’s five or six points and that on an IQ test may be something significant. Again it’s only two years. If we have that same thing in five years I would say it would be almost impossible that we wouldn’t be having an impact on the disease with the VTS-270 treatment. It’s all about how long in terms of time you can stabilize the disease. The Vtesse trial is for a year of the sham control usually trials are not sham or placebo control for as long as a year but because this disease is so slowly progressive that’s about the shortest amount of time we can expect to see change. In fact in the older onset patients are not allowed in the trial because their change wouldn’t even be enough in a year for us to see the difference. We might have to have a trial for two or three or five years. There are neurological diseases like that. One of the things this disease is helping us with is actually developing models for how do we do a trial in very gradually progressive neurological diseases and we can then use this information to understand how to approach other similar diseases.
You were saying the data you’re seeing is almost the same as past cases in the progression that you see and it starts to get worse. But then the people that are on this drug they’re not getting worse and some getting a little better.
Dr. Berry Kravis: I would say ours got a little bit better right after they went on treatment and then they kind of stayed the same for the past year and a half or so. But if their disease had been left to do what it does we would have expected them to get worse. I don’t think they’re following the path that natural history of their NP-C would predict that they would have followed.
You kind of touched on this so this may not be the cure but maybe it just gives more time.
Dr. Berry Kravis: Right. It might be that we’re going to stall progression and we don’t know how long. Maybe we’re going to stall progression for five years and then there’s going to start to be a more a gradual decline. Or maybe we’re just slowing it down so much that we can’t see it. We just don’t know those answers. Maybe in one person it’s going to stop the disease completely and in another person they’re still going to show more gradual progression. Again, we don’t know those answers and it’s a rare disease so we only have so many patients and it’s a little bit hard to figure out those answers. We’re going to need time to understand those kinds of answers. But I think anything that buys time while science develops better treatments is an important thing.
From what you’re seeing so far how do you feel about it?
Dr. Berry-Kravis: I feel good about what I’m seeing in the three patients who’ve been in my IND for two years. I feel like it would be unusual to see three patients not go downhill at all in two years with this disease. Hayley was so affected when she came in to the study and she was at a point where patients sometimes go downhill rather quickly because they start to get respiratory problems. She was starting to have all the choking and she might have to have a g-tube by now if she hadn’t gone in to the IND. So far I have been pleased with what I see, I hope it’s a long-term solution and I hope that it staves things off long enough that we develop other things to use in combination with it. The other patients that are in my IND have been in it for a shorter period of time so I don’t know what’s going to go on with them yet. We don’t know whether it’s going to work better for younger patients or older patients. We know the drug works best for cats that are less affected and we believe it’s going to work best for people who are the least progressed because there is a chance to save brain cells before they really get involved. We have a two year old in our IND now who we’re having the opportunity to treat before she really develops any definite brain symptoms at all. That is an opportunity for us to look and see if she ever gets the disease. We don’t know what will happen but we’re glad to have the opportunity to find out and that there is at least something we can treat her with for which there is hope for modifying the disease. For our older patients who are in their thirties we have the opportunity to ask does this work for people who are older or are they a little bit different in that the mechanisms going on in their brain are not as responsive to the medication. We hope that’s not true. We don’t think it will be true but we won’t until we test it.
Dr. Berry-Kravis: At Rush we have a total of seventeen patients, to be twenty by September, that we’re treating right now with every other week procedures and I think that’s more than any other place in the world right now.
Dr. Berry-Kravis: It’s a big effort to have these patients come in and do their procedures every two weeks. They come from all over North America. It requires a lot of orchestration, there’s a lot of other things we also have to monitor. The drug can cause hearing loss so we have to monitor hearing, and we have to monitor safety and make sure that nobody’s liver or kidney or anything is having a problem. We’re doing all of that as well as we’re monitoring all these different neurological areas of function to find out what’s happening to the patients in terms of their ability levels and their disease. It involves a lot of orchestrating a lot of people and a lot of things and luckily I have a marvelous support staff.
END OF INTERVIEW
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