RARE Daily

How One Patient Organization Leverages Research Investments

May 23, 2024

Tuberous sclerosis complex is a genetic disorder that is characterized by tumor growth in various organs in the body, as well as neurological effects. Most people with TSC experience epilepsy early in life and many develop autism or other neuropsychiatric issues. The TSC Alliance has invested more than $37 million in research since 1984. Its efforts and collaborations have resulted in six U.S. Food and Drug Administration approved treatments for some aspects of the disease or related conditions. We spoke to Steve Roberds, chief scientific officer of the TSC Alliance, about its success with crafting a research agenda, how it’s been able to invest in ways that catalyze research, and what it’s done to facilitate drug development by industry.

Daniel Levine: Steve, thanks for joining us.

Steve Roberds: My pleasure. Thanks Danny.

Daniel Levine: We’re going to talk about tuberous sclerosis complex, the TSC Alliance, and how the organization has constructed a multi-pronged research strategy to shape the future of treatments for the condition. Let’s start with TSC itself. For listeners not familiar with it, what is it?

Steve Roberds: Sure. TSC stands for tuberous sclerosis complex. It’s a genetic disorder. It’s caused by mutations in one of two genes. The TSC1 gene or the TSC2 gene. TSC can be inherited from a parent who has TSC, but actually two thirds of the cases are what we call de novo, or new. So they occur in families where TSC didn’t exist before. TSC is characterized by tumor growth in various organs in the body, primarily the brain, kidneys, skin, lung, heart, but also by neurological effects. So about 85 percent of people with TSC experience epilepsy and most of those very early in life, infancy. That can lead to learning disabilities if we’re not able to control the epilepsy. And also a lot of folks with TSC develop autism or other neuropsychiatric issues. So, it’s highly variable from person to person.

Daniel Levine: Does the condition progress over time?

Steve Roberds: It does progress. There are several things that can happen, and again, as I mentioned, it’s variable from person to person, but there are typical times during a lifetime where different things can happen. One is the growth of tumors in the heart, which can begin before birth. And so sometimes we’re actually able to find babies with TSC by a late stage ultrasound of the pregnant mother. They’re checking to make sure the pregnancy is developing and if a baby has TSC, it might have these tumors that are detectable in the heart and that can be an early sign, which is actually good if the baby’s going to have TSC, because then it can come to the attention of doctors and healthcare providers very early. So, the heart tumors are one of the earliest things after birth. There can be skin changes, so light spots on the skin. There can also be the development of epilepsy, as I mentioned, and can often start in infancy. There are tumors in the brain called SEGAs. That stands for sub-epidermal giant cell astrocytomas. These can cause problems, especially in childhood, but we do have treatments for those now so it’s less of a threat than it used to be many years ago. Also, in childhood adolescents can begin the development of kidney tumors, of tumors called angiofibroma on the face. And at puberty there can be a development of cysts in the lung that can lead to a disease known as Lam. There’s a longer name for it, but we can leave it at Lam. So really these things can happen throughout the lifetime. And then the neuropsychiatric issues can also occur at different times, whether that’s autism or learning disabilities or anxiety or depression. And so, some of these things can occur in adulthood and also childhood.

Daniel Levine: Given the risk of the development of tumors, do patients have to be monitored for this in some way?

Steve Roberds: They do, and there are consensus guidelines on the recommendations for how frequently to monitor and how to monitor. So MRI is commonly done both on the brain and then later in life in the abdomen to monitor the development of tumors in the kidney. In women with TSC, after puberty, CT scan is recommended to check for potential changes in the lung. So yes, there is a lot of monitoring that’s done.

Daniel Levine: What treatment options exist for the condition? Are they mostly to treat symptoms of it? And what’s the prognosis today for someone who’s diagnosed with TSC?

Steve Roberds: Great questions. So the main treatment option in TSC is a class of drug called mTOR inhibitors. These are useful in TSC because the lack of the TSC1 or TSC2 proteins leads to a lack of regulation of this enzyme in cells called mTOR. And so it’s overactive. So, these mTOR inhibitors are useful at compensating for the loss of TSC1 and TSC2. So they shrink the tumors, they stabilize the tumors. The thing is they’re not a cure, and if a person can’t tolerate the medications or has to come off of it, the tumors will start to grow again. So, we’re really at this point, while the mTOR inhibitors have had a major impact on the treatment of the SEGAs, of the renal angiomyolipomas, now the facial angiomas and epilepsy in some people, despite all of this, it’s really a lifetime therapy and not curative. There is another therapy developed specifically for TSC [that] is a pharmaceutical grade CBD or cannabidiol that’s called Epidiolex that’s used by many people to treat the epilepsy. It doesn’t work in everyone, but it’s helpful in some. And then there are a lot of other drugs that can be used for treating aspects of TSC, particularly the epilepsy. Vigabatrin is very useful, especially against infantile spasms, a special type of epilepsy that occurs soon after birth. And then there are other anti-seizure medications that aren’t specific for TSC but are used to help control seizures and TSC. There are surgical options for resecting a part of the brain that is causing the epilepsy. And there are behavioral therapies for aspects of the neuropsychiatric issues that one might also give to other kids without TSC who have autism or who have communication issues or learning issues or anxiety issues, et cetera. So there are a lot of therapies. The prognosis, there’s no reason a person with TSC can’t live a full life on average. They don’t. There are often complications, whether that’s from the lungs or the kidneys or the epilepsy that lead to premature death. But again, it’s highly variable. So the most important thing is really that early diagnosis and then that frequent monitoring according to the guidelines so that before anything can get too out of control, we have an opportunity to address it.

Daniel Levine: The TSC Alliance invested more than $37 million in research since 1984. Its research efforts and collaborations have resulted in six FDA approved treatments in the United States and available for some aspects of the disease or related conditions. As you think about the investments you make, to what extent are you able to leverage that by bringing other investments in behind you, and to what extent does that inform your investment strategy?

Steve Roberds: Yeah, great observation and question. It’s a very strong influencer of our research investment strategy where we tend to invest our dollars in the places that it’s harder for the even bigger funders to fund like the NIH. There’s also a tuberous sclerosis complex research program administered through the Department of Defense. I was looking at the numbers for 2023, and while they might not be final together, all of those, the NIH, the TSCRP, and the TSC Alliance funded about $37 million in TSC research in just that one year. So, while it’s taken us 40 years to spend that $37 million, the government is putting between $30 and $35 million a year into TSC research. And so we try to fund things that are different than what they can fund. They can fund the large projects. We work to catalyze research. We want to bring new investigators into the field. So, our grants program is focused on early stage investigators, people that are just completing their research training or starting their own new careers and research position. And oftentimes we can be the first research grant for that new investigator, and then they go on and they get additional NIH or TSCRP funding for their work. We also do a lot of investment into shared resources, so things like a natural history database where we collect clinical data on people with TSC, we collect bio samples from people with TSC. We have a preclinical consortium that has a set of animal models of TSC, and we are able to share those things with researchers, both in academia and in industry to really catalyze and accelerate the research of lots and lots of people rather than funding a number of specific research grants.

Daniel Levine: TSC involves a genetic pathway that plays a role in other diseases and disorders. You mentioned autism and epilepsy and cancer, but these conditions can exist without a person having TSC obviously. What effect has that had on your approach to research and your ability to attract funding to support it?

Steve Roberds: Right. So, because of those reasons [we] are big collaborators. We like to work with other groups who, as you said, don’t focus specifically on TSC, but who are interested in epilepsy in general or other rare genetic forms of epilepsy, autism, or other genetic conditions which lead to autism. And by collaborating in a variety of ways. This could be going to each other’s conferences. It could be by convening experts in all these different areas. It could be by co-funding some research. These are ways that we work together with these other groups to make all of our dollars go further and to help catalyze that learning across the groups. I would say we also, an example is there are some interagency collaboratives on both epilepsy and then another one on autism that we are a part of. So these have some government agencies, they have some large nonprofits, they have many small nonprofits who are parts of these collaboratives. And we share information and we talk about our successes and our failures and what we need and what we’ve done so that we can all learn from each other.

Daniel Levine: There are many rare disease patient organizations that are seeking to get involved in research and would love to replicate some of the success the TSC Alliance has had. How has the TSC constructed a research agenda and are there fundamental principles that define its approach?

Steve Roberds: Yes, there are. I would say the fundamental, I start with that, the first is we focus on the needs and the priorities of our TSC community on their unmet medical needs and what’s most important to them. The second thing is we work to catalyze research. As I mentioned, we fund shared resources that can be used by lots of investigators. So rather than investing in a number of individual projects, we build these shared resources so that other researchers don’t have to build on themselves. They can come in and they already exist. And then the third is we want to make it easy and attractive to work on TSC. So I was in the pharmaceutical industry before I came to the TSC Alliance, and one of the things that I thought of and I wanted was I wanted to make it so that if somebody else at a company had an idea for a potential new treatment in TSC, that they would see everything. We have the connection to the community, the shared resources, the experience and the knowledge and say, why wouldn’t I work on TSC? Let’s try it. Let’s go because the organization has all these things in place to help me.

Daniel Levine: Rare disease patient organizations have come to understand the critical role of data sharing. Do you place any requirements on researchers you fund to share data?

Steve Roberds: Yes, there are a couple examples of some requirements that we have. So first is with our grants program, we have basic data sharing requirements, much like the NIH, but we also provide through our membership in the Health Research Alliance, access to something called HRA Open, which is a free place to deposit data sets, draft manuscripts that people have created and make them available to other researchers. A second example is with our bio samples that we collect. So we have over 2,800 bio samples now, mostly blood, some tissues, DNA, et cetera. And when we share these with researchers, we do it at no cost to them. But what we do require is that they share their data back after they’ve done their experiments so that we will be building this repository of data to go along with the samples so that future researchers don’t have to repeat the work that was done before. They can access the data already there and then build upon that.

Daniel Levine: Rare disease organizations, in broad terms, make two kinds of research investments. The first is to enable drug development. The other is more targeted work around potential treatments and advancing them from the lab to the market. In terms of enabling drug development, I’m thinking here of things like natural history studies, animal models, bio repositories, and the like. What has the TSC Alliance done along those lines and how well established are the basic tools for de-risking drug development for drug developers’ pursuits of treatments for TSC and what has the organization done in that area?

Steve Roberds: Right, so we’ve got several pieces in place. So one, as you referred to, is the natural history studies. We have a natural history database that’s got more than 2,700 people enrolled. Currently it’s been operating since 2006. So that provides one resource. I’ve referred to the biosamples that we collect, and those are linked to the clinical data in the natural history database. So that’s available. That provides some resources for researchers to come in and start asking questions rather quickly about how does the disease typically progress? Can we identify any biomarkers in the blood? For example, in people with TSC that have certain aspects of the disease that they want to treat, we haven’t created so many animal models as we have collected animal models from researchers and made these available through our preclinical consortium to both academic and industry researchers. So that provides a way that researchers don’t have to establish their own colony and breed them up over months or years of time. They can work with us directly and we can accelerate that process of doing the experiments necessary to de-risk the projects. I think another aspect of de-risking is also really understanding the needs of the people affected by TSC, and I mean needs not just in what they need in terms of treatment, but if they’re going to de-risk their clinical trial, for example, they want to make sure that the clinical trial, the protocol, the frequency of visits, the requirements of being in the protocol that is the exclusion or the inclusion criteria, that those are suitable to the people that they want to recruit. Otherwise they have a high risk of not successfully even recruiting their study and then not getting an answer, which is certainly worse than getting a negative answer, is getting no answer at all. So through these various collections, I think we have a number of things in place to help researchers and drug developers de-risk along the way to treatments.

Daniel Levine: Talked a bit about how drug developers or researchers interested in conditions beyond TSC might have reasons for wanting to study it. To what extent have you been able to bring together different stakeholders to address common challenges in pre-competitive collaborations?

Steve Roberds: Right. So there’s a couple of examples come to mind. So one is through our preclinical consortium, which I mentioned has animal models, and we have contracts with contract research organizations who can run experiments on those models so that it really accelerates the process. They’re not just coming to us to share mice and we give them mice and then they have to do all the extra work. We already have processes in place to actually get experiments done. And so that’s been a way that is pre-competitive in the sense that we have had at least 23 companies partner with us since 2016 when we started doing this to utilize this resource. And we do that through a hub and spoke model where the TSC Alliance is the hub, and we have agreements with each of the companies that are members of the consortium. And that’s been a way to do it. So, they all have access to the same resources, but they’re not required to have agreements with each other. They’re not sharing data with each other necessarily. They’re not sharing, they’re not making agreements among themselves, but all of them are working with us. So, they all have access to the same expertise and the same materials. Another example is something called Anya’s Accelerator that we started last year, and this is to accelerate the development of biomarkers and outcome measures needed to identify new therapies that will work against the neuropsychiatric aspects of TSC. It’s a high bar, it’s a high importance to the community, and it’s also a very tough research question. And so we’ve been able to bring together and get input from people in academia, people in industry, some of whom have worked considerably in TSC and some who know what TSC is, but that’s not their focus. They work in mostly on other diseases. And so to get that broad input and those kinds of collaborations is very valuable for us and hopefully for the other diseases as well.

Daniel Levine: I suspect drug developers looking to enroll a clinical trial reach out to your organization. How do you work with them?

Steve Roberds: We work with a number of companies, as you mentioned, or drug developers who are planning a trial. And there are many ways. So one simple way is to look at their protocol and give them feedback on what’s likely to be attractive to community members who might participate in that trial or what’s likely to keep them out. We often set up meetings with them to talk directly with people living with TSC or with caregivers of children with TSC or dependent adults with TSC. And in some ways, especially with academic funded studies, we’ve done things such as partner to collect blood from the clinical studies or the clinical trial that’s ongoing. So, it’s available to the people doing that project, but then after the project, we already have it in our biorepository and can make it available to other researchers for other purposes related to TSC.

Daniel Levine: Where do you think patient advocacy organizations can have the biggest impact on drug development?

Steve Roberds: I think patient advocacy groups of all sizes can have an impact through communication. And here’s what I mean. So first there’s outward communication. This is to researchers, to companies, to the FDA about what are the unmet needs for your community? What are the research priorities from your community? Because that influences the future success of drug development. They need the patients to participate in the clinical trials to move the drug development process forward. And then I think the other way the advocacy groups can influence by communication is internally, and that is speaking to their own populations, their own communities about the importance of research and the importance of clinical trials and what to ask if there’s a clinical trial opportunity, what are the kinds of questions you should ask the physician who’s asking you to participate so that you’re educated and informed, and the community is aware of the importance of rigorous clinical trials, and that’s the only way that new therapies are going to be made available. So it’s critical that we have that two-way communication both outward about the priorities and inward about the importance of this research so that drug development can progress.

Daniel Levine: TSC is a genetic disease. To what extent are there efforts to develop genetic medicines to treat the condition, whether it’s ASOs, gene therapies, or gene editing?

Steve Roberds: There are genetic medicines in early stages, in the preclinical stages of development right now. TSC, as I mentioned earlier, is a genetic disorder, but two thirds of the cases are new, and that means they’re new variants. They weren’t inherited, so they’re different. And so, there are thousands of different variants or mutations in the TSC1 and TSC2 genes that can cause the disease. This means that it’s a great target for some approaches for gene therapy, and then maybe not so much for others. So the antisense therapies and gene replacement therapies, those are the things that are tractable in TSC and that are in these preclinical stages of development. So those are coming along. Gene editing is a bit different. That’s a tough one in TSC because there are so many different mutations and there are so many different tissues affected and trying to get the machinery to do the gene repair in every cell where it’s needed. That’s just a high bar. It’ll happen someday, I’m sure. But we have a lot of technical hurdles along the way.

Daniel Levine: What advice would you offer smaller advocacy organizations about how they could best create and execute a research agenda to address their diseases of concern?

Steve Roberds: My advice is to set a strategy that addresses the priorities of the community and to have input on that research strategy from many different types of stakeholders. So you, of course, need your informed community members and you need your academic researchers, and you need the clinicians who see lots of people with these, relatively speaking lots of people with these diseases and understand it the best. But you also want input from industry partners because the research that you’re doing, you want to facilitate drug development and drugs are eventually manufactured and sold by companies. So you want the engagement of the industry. The NIH has a lot of experience. People at the NIH see things going on in lots of different diseases. The FDA, right? That’s the end game. The FDA is going to need to approve any project. So you want at least some broad perspectives on a research strategy from them as well. And then of course, you can learn a lot from other organizations who have been there before and have tried certain things. And then it’s important to get all of this input and set a research strategy that really meets the needs of your disease, where it’s at this point in time, by learning from all of these different people with experience.

Daniel Levine: Steve Roberds, chief scientific officer of the TSC Alliance. Steve, thanks so much for your time today.

Steve Roberds: Thank you very much, Danny. It’s my pleasure and I appreciate you taking the time to talk to me.

This transcript has been edited for clarity and readability.


The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.


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