S4, E08: Moving FAST to Treat Angelman Syndrome

Jennifer Panagoulias (00:02): 
I always think about my own family situation because my niece is 20 and she was diagnosed about 17 years ago, and at that time it was incredibly overwhelming. There wasn't really much in the way of research. It didn't seem like anyone was interested.

Todd Poley (00:27): 
During a child's first two years of life, parents are observing their every move. How much are they sleeping? Can they roll from back to tummy? Are they learning how to walk and talk as they should? In our first season, we sat down with Dr. Allyson Berent, who shared her daughter Quincy's story about her Angelman syndrome diagnosis and her journey to find a cure for her daughter's rare disease. For Dr. Berent, she noticed subtleties in her infant daughter Quincy's behavior, like how often she smiled and how infrequently she cried. Doctors chalked up her behavior to normal developmental delays, but Dr. Berent followed her instincts and requested a genetic test. In doing so, she discovered that her daughter had Angelman syndrome, a rare neurogenetic disorder that can cause balance issues, motor impairment, and debilitating seizures.

As a mother and a clinician, Dr. Berent began to wonder, how many children exhibiting these same symptoms have gone undiagnosed and untreated? And what can I do about it? This propelled Dr. Berent to establish the Foundation for Angelman Syndrome Therapeutics or FAST in 2008. I'm Todd Poley, and in this episode of Vital Science, we talk with FAST head of regulatory and policy, Jennifer Panagoulias, on the progress being made in Angelman research, including the organization's unique interdisciplinary approach and a promising new gene therapy currently in clinical trials.

Gina Mullane (01:53): 
Welcome to Vital Science, Jennifer. We're honored to have you here today.

Jennifer Panagoulias (01:57): 
Thanks, Gina. I'm really excited to be here today.

Gina Mullane (02:00): 
So why don't we jump right in and would you please tell us about yourself?

Jennifer Panagoulias (02:04): 
Sure. I am the head of regulatory and policy for the Foundation for Angelman Syndrome Therapeutics, and my background is in regulatory affairs. I've worked in the biotechnology space for 24 years for a number of different companies with development programs to treat rare diseases, but my most important role is that I am the aunt to a young woman with Angelman syndrome. Her name is Samantha. And it is really my connection and my family's connection to rare diseases that brought me to the foundation.

Gina Mullane (02:41): 
Given your broad experience, what are the challenges like working in a large corporation as compared to working as part of a foundation? What's the difference there from your perspective?

Jennifer Panagoulias (02:53): 
Well, the big difference is resources, that's what comes to mind initially. Because in a small foundation you have limited staff, limited funding to really carry out your objectives. And a lot of times we have to wear a lot of different hats to figure things out, to attack projects the way that we want, to make sure things happen quickly. At FAST or the Foundation for Angelman Syndrome Therapeutics, we like to say we're called fast for a reason, so we like to move quickly and you need resources to do that. In my personal experience in industry, I worked in really large companies including a hundred thousand person company. And there you have ample resources to generally to carry out the job, although you spend a lot of time getting through red tape and formal committees to do that. So I think speed is sacrifice there, but you have a depth of resources to really get things done when you need to.

Gina Mullane (03:55): 
Well, I love that your acronym also translates into how you approach solving problems. That's wonderful. And so how did the Foundation for Angelman Syndrome Therapeutics get started?

Jennifer Panagoulias (04:08): 
It was started in 2008 by a group of parents of children with Angelman Syndrome who really wanted to see funding for Angelman syndrome translated into potential therapies. And so they wanted to really see efforts that they had undertaken to raise money, go to funding potential cures, and not just for support services or educational services. And those are all important by no means to say they're unimportant, they're very important aspects, but they really wanted to see research into action and to have the potential for therapies for their children. And so they had different backgrounds in business, science, finance, and they brought together that passion and that expertise to really start the foundation and really direct it towards cures.

Todd Poley (05:03): 
And it's this vision to see critical research translated to the clinic that drives FAST mission forward, not only from a scientific standpoint, but a funding perspective as well. FAST leadership team is careful to use the organization's funds wisely by aligning with researchers who have the most promising strategies with a diverse set of targets. Meanwhile, members of the FAST community are continuously fundraising with everything from tournaments, walks and bake sales to gala nights, auctions and investor engagement. The organization recently received a donation of nearly $6 million to help translate key programs into action. Let's hear more from Jennifer on this initiative.

Gina Mullane (05:45): 
So I read on your website about the FIRE consortium or FAST Integrative Research Environment that works collectively to find treatments for Angelman syndrome and ultimately a cure. How has FIRE helped to advance Angelman syndrome research?

Jennifer Panagoulias (06:02): 
I think it was an amazing idea to bring together an integrated research team that had different specialties and disciplines. And I think what's helped there is instead of having everybody working off in their own world, it brought them together periodically to share their learnings and their research in Angelman syndrome and to create a sense of team so that they were working collaboratively to help solve the problem, but also focusing on their specialties, which may have been genetics or gene therapy or epilepsy or animal models. And so they were trying to bring to the table their own expertise in their specific discipline that would in turn help somebody else at the table with a project they had. And so I really think at its base level, it was about team building within the community, within the academic community to help people work together and share so that knowledge was broadly used.

I mean, I think one of the most amazing things that came out of that team was that one of our researchers had done a tremendous amount of work looking at the UBE3A gene and studying that region that eventually led him to develop an antisense oligonucleotide to target a key region of that gene in an attempt to un-silence the paternal allele as a treatment strategy. And we can talk about the genetics of Angelman syndrome, but essentially he was a pivotal member of that team and his work translated into a potential therapeutic that is now in phase one, two clinical trials.

Gina Mullane (07:53): 
That's got to feel good to reach that level of accomplishment. We started and dove right into the organization, but if you don't mind, I want to take a little step back and you mentioned your personal connection to Angelman syndrome. I know that it's a rare neurogenetic disorder. Can you tell me a little bit more about it?

Jennifer Panagoulias (08:13): 
Absolutely. Angelman syndrome is a neurogenetic disease that is caused by a mutation in a gene called UBE3A. I think it helps to start with the fact that UBE3A is unique because it is imprinted in the central nervous system. And so in every person, we obviously have two copies of UBE3A and you get one from your mom and one from your dad. But in the brain, in neurons, the mom's copy expresses all of the protein that we need and the dad's copy is imprinted or silenced. So it means that nothing is being expressed from the dad's gene in the brain. And so in patients with Angelman syndrome, when they have a mutation in the UBE3A gene that leads to lack of expression, it gives rise to all of the symptoms of Angelman syndrome because there's no mom's gene in most cases, about 80% of patients have that gene deleted or it's mutated and not producing protein the way it should, and then you get nothing from your dad.

So your dad's turned off and then moms is missing. And so it gives rise to the neurodevelopmental aspects of Angelman syndrome like seizures, ataxia, lack of communication, cognitive disability, sleep disturbance, and a number of other symptoms.

Gina Mullane (09:42): 
And are those characteristics and symptoms evident right away, like right at birth, or is that something that over time you start to see more and more of those things surface?

Jennifer Panagoulias (09:53): 
It presents really early in life, and I can draw from my own family experience to say that my niece, when she was born, it was evident very early on that there was something amiss because she had extreme feeding difficulties. She didn't gain weight and she didn't reach developmental milestones very early on. And I think the challenge is recognizing is that what it is something wrong. Are they really behind in terms of their development? But generally it presents very, very early in life. Sometimes it presents with severe epilepsy in very young children, and so that might lead them on a faster path to diagnosis but it's pretty evident. Most children, I believe, at present are diagnosed by two years of age.

Gina Mullane (10:43): 
And do you know what the criteria is to test for Angelman syndrome?

Jennifer Panagoulias (10:48): 
It's so dependent on the clinician to decide whether they're going to test them or how they're going to evaluate. So these children don't meet developmental milestones. And what the doctor does at that point is really, I think, up to them. And I have a really close colleague who is a pediatric geneticist at Boston Children's Hospital, and what she said to me is, unfortunately, pediatrics is a discipline of wait and see. And so that really influences in some cases how long it takes to be diagnosed. And obviously Angelman syndrome is also rare, so you may not be thinking that that is the issue, you may have never have seen that before. So it really depends on the physician. I'm hopeful that with changes in screening and genetic testing programs and the access to screening panels and different test panels, that there will be broader access to testing at an earlier age that really could help diagnose patients without having to go through a long diagnostic odyssey.

Todd Poley (11:57): 
Angelman syndrome is not the same experience for every patient. The disorder can present to varying degrees with the most severe clinical phenotype being gene deletion. This accounts for about 80% of patients, but 20% have mutation in the gene leading to deficient protein or uniparental disomy, meaning you can get both genes from a single parent. Research suggests that the more severe the mutation, the more severe the clinical condition. This is why the folks at FAST like to say a little bit goes a long way. Therapies that lead to even modest improvements in UBE3A expression can change the life of an Angelman patient and their family. Let's get some more insight on this from Jennifer.

Gina Mullane(12:41): 
So you've described many of the conditions that come along with the syndrome. What is life like for those patients and their caregivers as time goes on?

Jennifer Panagoulias (12:53): 
It's very challenging for caregivers of children with Angelman syndrome because they really cannot live an independent life. They really require constant care and vigilance. There's obviously a lot of medical involvement. They have seizures, they have ataxia, they have communication disorder that requires occupational therapy. They need physical therapy, they need behavioral therapy. So it's very hard to care for them. And so we obviously know about all the clinical manifestations, but what doesn't really get talked about in terms of a caregiver is that it can be really socially isolating because children with Angelman syndrome also have behavioral difficulties and they might have outright behaviors like hair pulling or biting and it's really difficult. And so sometimes I can speak from my own family experience, it's hard to want to go to the movies or go to a museum because they might not behave appropriately in that setting and people make comments or people stare.

And so it's hard. And so there's the aspect of social isolation. There's a lot of anxiety and depression, and there's also a huge impact on sleep. Children with the Angelman syndrome do not sleep well. They don't sleep a normal amount of time at night. They have trouble falling asleep, they have trouble staying asleep, and so the child doesn't sleep and the family doesn't sleep. And that takes a massive toll on your day-to-day as a caregiver. So it's really an intense environment that requires a lot of assistance and a lot of resiliency.

Gina Mullane(14:46): 
On your website, I saw that the modalities that you were pursuing included the [inaudible 00:14:52] that you mentioned already as well as small molecule. Can you tell us about those pathways and what you see as the prospect for treatment in the future?

Jennifer Panagoulias (15:04): 
I think there's a lot of hope towards the future regarding treatments. We are focused on a couple of therapeutic pillars at FAST, and we simplify them down to fixing the mom's gene and fixing the dad's gene. Obviously the antisense oligonucleotides are targeted at really addressing the issue at the dad's gene level. So basically strategies that involve targeting this long non-coding RNA transcript that silences the paternal allele. And so there are ways to address this through knockdown, through an antisense oligonucleotides that hits that antisense transcript that's silencing the dad's gene to allow it to be expressed. There are CRISPR strategies that are focused on permanently knocking down that antisense transcript that silences the dad's gene. And then we look at mom targets or fixing mom's gene targets, and those would be gene therapies, gene replacement therapy through AAV mediated therapy or through lentiviral therapy to really cross correct and express UBE3A permanently. That's what our hope would be.

Todd Poley (16:23): 
Angelman syndrome affects approximately 500,000 individuals worldwide. It is believed that in the United States, the incidence is about one in 15,000, but FAST believes that number may be closer to 27,000 due to under diagnosis. There's no definitive age when Angelman diagnosis is made and the journey to being diagnosed is not always easy or straightforward. So far, about a thousand patients have registered with FAST, in registering they receive a welcome packet, educational resources and ways to connect with the FAST community. Simply getting the word out to patients and ensuring they have access to these resources and future treatments is a large part of FAST's mission.

Gina Mullane (17:06): 
In other podcasts that we've done, we've talked a lot about patients accessing treatment and becoming aware of these groups that can help. How do you think we can make access to treatments better for patients easier? Do you have an opinion on how we can approach that?

Jennifer Panagoulias (17:27): 
Well, I think one of the issues is price. We want to make sure that if drugs are approved, they can be reimbursed and accessed by patients. And I know that that's a complicated process, obviously. It's something that we think about at the foundation because we really don't want to get to a point where there are therapies, but nobody can use them. So we try to understand what our role might be in that process. And one of the things that we've undertaken is an economic burden survey where we're reaching out globally to the community to understand what are the economic burdens of care to really show that it's not trivial in terms of what a family is spending on symptomatic treatment. So they might take anti-epileptic drugs, they might take behavioral and anxiety medicines, they need equipment, they need support services, they need home health support, personal care aides and things of that nature.

It's super complicated to maintain all of this care and it's expensive. So we are trying to collect information so we can robustly establish what is the lifetime cost of care. Something that isn't talked about a lot is because of the lack of independence in the long term. There are adults with Angelman Syndrome who may be in long-term care facilities, and that's obviously a huge economic burden. And so that needs to be factored in. So we're trying to help really establish what those costs of care are so that it can be considered relative to access, so that pricing can be evaluated in the context of what it really costs to care for a person with Angelman syndrome over their lifetime. And hopefully it will be shown that it's far cheaper to just give them the drug than to not.

Gina Mullane (19:25): 
Thank you for that. That was really helpful. I don't think I have ever thought through it in that way before. I know an area of expertise for you is certainly the regulatory requirements and approach to making sure that that path is clear and effective and managed appropriately. Can you tell us about the regulatory pathway for treatments, medications in the field of orphan diseases? What does that look like?

Jennifer Panagoulias (19:59): 
Well, one of the challenges I think coming from my background in industry is developing the outcome measures to get you to an approval. So obviously you need therapies, but then you need tools to be able to measure the effect of those therapies. And in my different time at companies when we may be looking at therapeutic opportunities, maybe there's a partnership or maybe we are trying to understand the application of our technology in a certain area and say, "Oh, well, how might we apply this to X disease?" We look at the science, we look at the opportunity, but also we're looking at the regulatory pathway. We're trying to understand, has anyone been there before? What will we measure? Are there tools to measure it? Would it be hard to measure? Are there end points we don't like because we think that the regulatory authorities would not be supportive of them?

So we consider the regulatory developability too. So I think one of the best things that FAST has done was to try to develop or identify existing outcome measures that could be used to measure change in clinical trials that would be sufficient to get the drug approved. And so that's one of the most important things really that they've done, is to create a list of potential outcome measures and biomarkers that could be utilized to advance a drug to registration. Because having endpoints and things to measure that have regulatory acceptance by FDA or the European Medicines Agency will help bring people into the space because they don't have to create it all themselves. So that's something we think about, we think a number of different opportunities like, how can we show change and can we show it across a number of symptoms because we don't know what will be the one outcome measure that that can be considered as a primary endpoint for registration purposes. So we're trying to create a toolkit where there's a number of options that one could use.

Todd Poley (22:08): 
FAST has taken an interdisciplinary approach to solving this problem. Together with the Angelman Syndrome Foundation and Agile Biopharmaceuticals, the organization established an outcome measures consortium called the Angelman Biomarkers and Outcome Measure Alliance or ABOM. ABOM is a pre-competitive group that includes academics, advocates, and industry professionals who have come together to identify the best ways to measure clinical progress in Angelman syndrome and design better trials to test the effectiveness of new experimental treatments. The academics in the group are able to share observations on what they have been seeing in patients and industry veterans can speak to what has been utilized in trials for similar therapeutics or previously gotten traction with the FDA. Leveraging their collective expertise, the group is working to hone in on the most promising set of outcome measures and weed out those that are unlikely to demonstrate change or are too complicated for use in multi-center trials. Let's hear more from Jennifer on other valuable partnerships that are helping FAST push their mission forward.

Gina Mullane (23:12): 
So in what ways can collaborating with a contract research organization help programs like yours?

Jennifer Panagoulias (23:21): 
Well, those relationships are really valuable because with limited resources, we do not have testing capability at FAST for sure. And so our relationship as an advocacy organization with Charles River has been hugely helpful to us for a number of reasons, including access to expertise, to provide guidance, and to help provide feedback on some of our funding opportunities to evaluate programs for us, to have testing infrastructure, to evaluate candidates, whether it may be through academic groups that we're working with who don't have their own capabilities. And so we know that we can rely on our partnership in particular with Charles River to help screen potential compounds or to test things in toxicity studies, to develop analytical methods. It's really important for us, and what I think is amazing is we've developed deep friendships with people on the team who I feel are bought into the mission and care about Angelman syndrome as we do. And they've developed expertise in this area that helps us and they can in turn help others based on that knowledge. So it's really important. Those relationships are really critical for us.

Gina Mullane (24:46): 
I know many of those people probably have met patients that you're working with, and it has become an even more personal kind of mission for them, I expect. What does the future hold for Angelman syndrome research?

Jennifer Panagoulias (25:02): 
So much promise. I always think about my own family situation because my niece is 20 and she was diagnosed about 17 years ago. And at that time it was incredibly overwhelming. There wasn't really much in the way of research. It didn't seem like anyone was interested. And I worked in industry, and so I had access to information about different companies that could be considering opportunities. And it seemed as if there was absolutely nothing and no hope. So through the efforts of the foundation to really grow a strategy to attract academics and industry into the space through the development of animal models, through partnerships, through outcome measures, it has changed dramatically. I mean, today there are four companies with active clinical trials in Angelman syndrome. And so I think the future is so promising, and the collaborations that we have will absolutely lead to a multiple therapeutic approach or multiple therapies in the future. I'm absolutely convinced that in the future, my niece and other people with Angelman syndrome will have the opportunity to access a number of treatments.

Gina Mullane (26:21): 
And do you foresee that those treatments are translational to any other neurogenetic disorders?

Jennifer Panagoulias (26:28): 
Well, I think what we're learning will have applications other neurogenetic disorders. I certainly think that what we're learning about measuring outcomes can be utilized for other neurodevelopmental disorders. And so in particular, we spent time developing an outcome measure to look at communication. About 80% of children with Angelman syndrome will never develop any verbal communication skills in their lifetime. And when we looked across the space about what was out there to measure communication, because it's so, so important to families. Multiple surveys have shown it's the most important symptom that families want to see changed by therapeutic. We saw that there was really nothing that was fit for purpose to measure communication ability in non-verbal individuals with Angelman syndrome. And so we work together with Duke University to develop an outcome measure, and it's called the ORCA or the Observer Reported Communication Ability Measure, excuse me.

And that is something that's being piloted in clinical trials of Angelman syndrome, but Duke was funded by FDA at almost $4 million under a patient focused drug development grant to take the ORCA and repurpose it for use in other neurodevelopmental disorders, in particular 12 other NDDs. So I think we're learning about how to use these measures and apply them in other disorders, and I think establishing the regulatory pathway there is going to benefit many, many other NDDs that are now early in their therapeutic development.

Gina Mullane (28:11): 
Well, I'm very inspired by all of the positive work that's being done. I feel very hopeful. What does the year ahead look like for FAST?

Jennifer Panagoulias (28:23): 
And so what we're looking to do is really build for the future to be an organization that can support both translational research but also other caregiver needs, and to pave the way for access that we've already talked about in terms of our ability to express the unmet medical needs for patients and to support the burden of care and the cost of care to help drive access to therapies. So that's really an important part of what we'll do as well as continue our efforts to promote genetic testing through our search and rescue initiative, and that's really intended to help us find those undiagnosed patients.

Gina Mullane (29:06): 
Wonderful. So how can the listeners of Vital Science help you and FAST to get there?

Jennifer Panagoulias (29:13): 
I think that the listeners can help us by driving awareness of Angelman syndrome. And I know that's a tall order, but I think awareness of these disorders, not just Angelman syndrome, but all neurodevelopmental disorders will really help us think about how to collectively find and support these communities more holistically.

Well, we'll do everything we can to bring visibility and spread the word.

Jennifer Panagoulias (29:50): 
Thank you. I appreciate that.

Gina Mullane (29:52): 
Well, thank you so much for being here with us today on Vital Science, Jennifer.

Jennifer Panagoulias (29:57): 
Thank you so much. It's been a pleasure to talk to you today.

Todd Poley (30:01): 
Jennifer Panagoulias is the head of regulatory and policy at the Foundation for Angelman Syndrome Therapeutics. Looking ahead to our next episode of Vital Science. In June, we'll talk with Greg Classen, a patient living with spinocerebellar ataxia type 3 about how he and his son Jeff, who also lives with the disease, are working with Cure Rare Disease to raise $5 million to develop treatment to slow or reverse the symptoms of SCA3. Did you know that Charles River has a sister podcast, Eureka's Sounds of Science? This monthly podcast shares scientific, patient and advocacy perspectives on trending issues in the drug development industry. You can subscribe to Vital Science and Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts. Until then, thanks for listening.