Interviewer: Audrey Davidow Lapidus, PHRF President, and mom to Calvin
Those of you who are new to Pitt Hopkins and the Pitt Hopkins Research Foundation might not be aware of the work accomplished by Dr. David Sweatt at the University of Alabama, Birmingham. Dr. Sweatt was our first funded researcher and the first laboratory researcher in the United States to begin studying Pitt Hopkins just three years ago.
When my son Calvin was diagnosed (at the age of one) in March of 2012, I was beside myself with grief and an overwhelming urge to do something. So I started researching furiously on the internet. I was dismayed to find no one was researching Pitt Hopkins. However, I found that researchers working in similar syndromes, like Angelman and Rett, had found a way to reverse the symptoms of these disorders in mice. I read an article about a particular Angelman’s researcher who had been able to reverse symptoms and was about to launch a clinical trial! In that article, he gave a great deal of credit to his mentor and teacher Dr. David Sweatt. So I thought that’s who we need researching PTHS, we need that guy’s teacher!
Out of blue I wrote to Dr. Sweatt. It’s probably a good thing I didn’t know then what a scientific big wig he was, otherwise I would have never had the guts. I wasn’t really expecting him to respond to my desperate email. But he did. Within 12 hours he responded and said he would help us in any way he could.
With Dr. Sweatt on board, we started fundraising and two months later we awarded his lab our very first grant. Part of the money was meant for him to hire a team of top notch post docs to dedicate their research and career to PTHS. He found that in Dr. Andrew Kennedy, Dr. Cristin Gavin and Dr. Elizabeth Rahn. They will always hold a special place in my heart as our first funded researchers.
So now that you have a little history, I wanted to share with you all what they have been up to lately.
Q. What first interested you about researching Pitt Hopkins?
Dr. Sweatt: From a neuroscientist’s perspective it is a fascinating disorder to try to understand in terms of underlying genetics. It was right down my alley in terms of the kind of work that we have ongoing in my lab. When I started reading the literature and educating myself about the disorder I became more interested in it as a neuroscientist but also committed to the idea that somebody needed to do something about this disorder and try to begin to develop some avenues for potential treatments for this very debilitating disease.
Dr. Kennedy: Generally, in neuroscience, what you’re studying is a very complicated disease or disorder, like Alzheimer’s for instance, where you have hundreds, if not thousands, of genes playing a part. When considering epigenetics as a potential mechanism to treat deficits with learning and memory, it’s ideal to target a syndrome that’s caused by a single gene, because then you can really understand the system. Pitt Hopkins is extremely interesting because we can take what we’ve known about epigenetics and epigenetic therapies and have a compact model, a test case, where we can understand the genetics, the biochemistry.
Q. So, today, three years later, what is it about Pitt Hopkins that keeps you motivated and interested to continue the research?
Dr. Sweatt: The thing that gets me most motivated is the data Andrew has generated. Andrew has made a lot of exciting discoveries in terms of the underlying mechanisms in the brain that contribute to both the social interaction differences and the learning disabilities that are associated with syndrome. The most exciting work recently is the discovery that certain kinds of epigenetically targeted drugs are improving some of the learning and memory difficulties in the PTHS mouse model, and of course that gives us some hope that this type of therapeutic avenue might someday hopefully be beneficial for Pitt Hopkins kids.
The other thing that’s really exciting is the way that the neuroscience community has really engaged in the problem of trying to understand Pitt Hopkins syndrome, that there’s a vigorous group of scientists now in almost 10 different labs that are really interested in Pitt Hopkins and trying to understand it and develop new therapies when just three years ago really no neuroscientist, me included, had ever even heard of Pitt Hopkins syndrome.
Q. Can you explain what epigenetic mechanisms are?
Dr. Kennedy: When we say epigenetics, we’re referring to how the genes which are written for you at birth are packaged and how they’re accessed by the rest of the organism. Epigenetics can alter whether or not this gene is easy to read or difficult to read, even how it’s read; whether it’s read completely or partially. That can have profound effects in how that gene functions in the cell. In a case like Pitt Hopkins syndrome where you have one viable copy of TCF4 and one non-functioning copy, epigenetic therapies are particularly interesting, because if you could use a therapy to make TCF4 easier to read, you could possibly read the good copy twice as much. Essentially you would be reconstituting the level of TCF4 needed in an adult functioning central nervous system.
Dr. Sweatt: One of the things that we have discovered in the lab is that these epigenetic mechanisms that control the three-dimensional structure of genes are involved in normal learning and memory processes, and it turns out that some of those same mechanisms are disrupted in the mouse model of Pitt Hopkins. So we have now an understanding of at least part of the mechanisms for the learning disabilities associated with Pitt Hopkins syndrome. Of course, the hope is that our understanding of that mechanism will allow us new types of ways to think about drug therapies that might be beneficial, that is, drugs that target those particular epigenetic mechanisms.
Q. The Pitt Hopkins Research Foundation first funded your lab in the spring of 2012. Can you tell us a little bit about what that funding has allowed you to accomplish?
Dr. Sweatt: In the broadest sense, it allowed us to even get going at all, because there’s a catch 22 in terms of generating research dollars from any of the government granting sources. You have to have some evidence that your ideas will work before you can even apply for funding from the government to do biomedical research. If you don’t have any seed money, you can’t even get the ball rolling. The Pitt Hopkins Foundation and the private family’s donations to the lab in the very earliest stages allowed us to get that core of very early data that proved that Pitt Hopkins was something you could even reasonably work on in terms of laboratory biomedical experimentation.
Dr. Kennedy: Three years ago when I came to Dave’s lab, the first thing we did with the seed money was acquire these mice, which miraculously had already been produced for a non Pitt Hopkins purpose. TCF4, as a gene, was studied in immunology for several years and someone had generated a mouse model and never characterized it for any of the phenotypes seen in Pitt Hopkins syndrome. So three years ago, we were a little bit anxious because we didn’t know if the mice would even model the syndrome. It turns out that they do – quite incredibly. They mimic the cognitive deficits, they also have motor deficits, they even share the constipation of Pitt Hopkins patients. These mice have lower velocities for excreting dyes, which is the specific experiment we ran to show that they have slower velocity GI tracts. It’s been pretty incredible that the mice model the syndrome so closely.
Q. Do the mice show breathing and seizure behaviors?
Dr. Sweatt: That is something we are working on right now with collaborators. We want to look at spontaneous seizures and use EEG’s to see where the seizures are coming from if they were occurring. Qualitatively, though, we can see that the Pitt Hopkins mice have seemingly more seizures than the wild type animals, but we haven’t done a thorough study on that yet.
Q. So you get the mice and you study them and indeed they do seem to mimic Pitt Hopkins as we know it in the human condition. Then what do you do?
Dr. Kennedy: After about 6 months, when we felt the mouse model was accurately modeling the human condition, we could do two very important things. First, we now have a system by which we can test therapeutics. We have a measure with a baseline, and we know what wild type animals do, what Pitt Hopkins animals do, and the gap we need to bridge with some kind of therapy. Also, coupled with that, as far as picking therapies, we can use the animals as subjects to understand the biochemistry of Pitt Hopkins syndrome. Yes, Pitt Hopkins Syndrome is caused by having one copy of TCF4 that’s been mutated or deleted. However, that’s not saying a lot about how to treat the syndrome. If you’re trying to find a drug that can go in and improve the cognition of people with Pitt Hopkins syndrome, you have to understand what the consequences of having one copy of TCF4 mutated or deleted means. Because the mice model the cognitive deficits in the other aspects of Pitt Hopkins syndrome, any information we can learn about their biochemistry should transfer to the human condition as well.
Q. Is there anything about their biochemistry that you’ve learned that you can share at this point?
Dr. Kennedy: Sure. It’s going to be a little technical, but as simply as possible, we noticed disregulation in the expression of types of glutamate receptors. Glutamate receptors are truly important in many aspects of the brain, but especially in memory and learning.
One of the other things that we found, and we have more evidence for this one, to be disregulated biochemically was DNA methylation, which is an extremely important epigenetic mechanism in governing formation and consolidation of long-term memories.
Q. So we can test drugs that may ameliorate these things?
Dr. Sweatt: A blessing and a curse of using a genetically engineered mouse model for disease is that you can test out drugs that are available that you can use in the lab, but that have not been approved for use in humans. The advantage is you can try out different kinds of drugs that aren’t really safe for use in humans to see whether those types of drugs might be doing something beneficial in the Pitt Hopkins mice. That’s where we are with these studies. We have access to chemical compounds that are pre-drugs, that haven’t been approved for use in humans by the FDA that we can test out in animals and we have some encouraging results. The down side of that, the curse so to speak, is that then we don’t have some of these drugs or anything that we can take into a human being right away. It just gives us categories of drugs that look promising that we can use to guide future efforts to begin, for example, to screen drugs that might be more likely to be approved for use in humans. That’s where we are with the drug studies at this point.
Q. So it’s more like, “Okay, well we know that this drug worked, but it’s not really ready for human consumption, but let’s look at this other drug that may be FDA approved but sort of similar?”
Dr. Kennedy: Exactly. It takes so long to test a molecule in a mouse versus a cell line or even in fish, so you want to make educated guesses where you’re going next rather than blindly screening.
Q. Last summer the National Institutes of Mental health awarded you a large grant to study Pitt Hopkins. What will you do with that money?
Dr. Sweatt: It makes a huge difference to have that level of funding so that we can pursue more of the ideas, especially trying out different kinds of potential therapeutic approaches and doing a deeper dive in terms of trying to understand how these epigenetic mechanisms are involved. There’s that practical side to it, but the other thing that’s really important is that it really gives a national level stamp of approval to this type of Pitt Hopkins research.
Q. Is it fairly unusual for a disorder as rare as Pitt Hopkins to get that kind of funding from the NIH?
Dr. Sweatt: It certainly makes it more difficult, because one of the criteria that grant reviewers use in deciding whether to fund or not is, “is this going to affect a lot of people who have a disease or is it only going to affect a few?” It’s an investment of taxpayer dollars and like any investor, they want to maximize their investment. In the case of the Pitt Hopkins grant that we got, we were able to articulate to the reviewers that yes, we’re studying an orphan disease, but anything that we learn about Pitt Hopkins with the intellectual disabilities and the social interaction differences might be directly relevant to a wide variety of different types of developmental disorders, like Autism. Anybody who gets a toehold on understanding learning disabilities is potentially going to be able to leverage up a lot of understanding for other more prevalent diseases as well.
Q. Where does Pitt Hopkins Research stand in comparison to other similar disorders at this point?
Dr. Sweatt: Part of the reason why Audrey contacted me to begin with was because I had a history of working on Angelman’s syndrome which is clinically very similar to Pitt Hopkins. I would say that the Pitt Hopkins research community that exists now has made tremendously rapid progress in advancing our understanding of Pitt Hopkins syndrome. I would say that even though other related syndromes, like Angelman and Rett had a huge head start on us in terms of the amount of time that people have been working on those syndromes, that we’ve played a great game of catch up that is really quite astounding to me, having worked in these areas for almost 25 years. .
Q. Do you believe the improvements you’re seeing in the mice could help adults with PTHS as well?
Dr. Kennedy: We test in young adult to adult mice and we’re seeing these improvements. So, theoretically speaking, yes we would expect these therapeutics to bring improvement to adults too.
Q. What’s next for your research?
Dr. Kennedy: We want to further understand how these classes of epigenetic drugs are correcting or affecting the disregulated biochemical mechanisms that we’ve observed in the mice, and then how more specific targeted small molecule drugs that are FDA-approved might function in the same way.
Dr. Sweat: One of our immediate goals is to evaluate other additional new types of therapeutic approaches, different types of compounds that would be more readily applicable for humans. I think that’s a real high priority for us right now and obviously it’s going to be for the families as well.