A Software Platform to Give Patients the Tools to Build Treatments for Rare Genetic Diseases

Sanath Kumar Ramesh’s son Raghav was born with an ultra-rare and progressive disorder known as SSMD. The condition is caused by mutations in the GPX4 gene. There are only a handful of known patients with GPX4 mutations. In the past, most known cases resulted in death about a month after birth. Ramesh has moved with remarkable speed to find patients, raise money, and drive research. But he also realized that many other parents of children and small, rare disease organizations must go through the same process to develop treatments for ultra-rare conditions. To guide and accelerate the work for others, Ramesh has created OpenTreatments Foundation, a nonprofit with a software platform to enable treatments for genetic diseases regardless of rarity or geography. OpenTreatments provides people with a road map for developing genetic medicines; connects them with researchers, clinicians and other needed to advance their programs; and helps them show their capabilities to raise funding despite the rarity of a condition. We spoke to Ramesh, founder of OpenTreatments Foundation, about how his software platform works, the need it addresses, and how it can accelerate the development of treatments for ultra-rare genetic diseases.

Daniel Levine: Sanath, thanks for joining us.

Sanath Kumar Ramesh: Thank you so much for having me. It’s a pleasure.

Daniel Levine: We’re going to talk about your nonprofit initiative, Open Treatments, how it’s seeking to enable patients and their families to pursue the development of therapies for ultra-rare conditions. Before we get into the specifics of Open Treatments, I thought we could talk about what led you down this path. What happened when your son Raghav was born?

Sanath Kumar Ramesh: My son was born two and a half years ago. When he was born, just a few hours after birth, the doctors noticed that there was something abnormal going on with him. They did not know what was wrong with him at that time. So, we started going through this diagnostic odyssey, which ended after a year. We spent several days in the hospital after birth going through a lot of tests, but the blood work did not give us any results. Then the doctors asked us to go through genetic testing and whole exome sequencing. After two misdiagnoses, we ended up with the correct diagnosis for my son’s condition, which was that he has a mutation in a gene called GPX4. At the time he was diagnosed, we didn’t know of any other kids with this disease. Since then, we have identified several other kids with this disease, and we estimate there are nine kids in the world living with this disease. I’m sure there’s a lot more we are yet to find.

Daniel Levine: What was known about the GPX4 mutation, if anything?

Sanath Kumar Ramesh: There was nothing known. In fact, when we got the diagnosis, our doctor handed us a paper from 2014 and that was the last paper written about this disease. The paper was reporting about two kids who passed away just a few weeks after birth and their sequencing revealed a mutation in GPX4. Since then, we have done a lot of research and now understand the mechanism of action of GPX4. We have completed a lot of drug repurposing activities and gotten my son started on a cocktail of five different drugs. We are pursuing other drug repurposing activities as well. All of these are giving us more clarity into the mechanism of action of this disease. Nevertheless, this is only the tip of the iceberg and there’s a whole lot to be explored.

Daniel Levine: What are the consequences of this gene in the case of your son? What’s known about it today?

Sanath Kumar Ramesh: My son, specifically, has severe hypotonia, which means that he cannot move his head, he cannot lift anything with his hands, not even a small toy or a metal spoon, he cannot stand, sit, walk, or run like most normal two-and-a-half-year-old kids. It also means that he has severe swallowing difficulties and inability to speak. In addition to all the neurological problems that he has, he also has severe skeletal dysplasia, which is the hallmark of this condition. His long bones have abnormalities, his spinal cord is not developing properly, and he has scoliosis and kyphosis. So, his resume of medical challenges is longer than my resume of work.

Daniel Levine: This mutation is so rare. You say you now have identified a handful of patients with the condition. What does this mean for the prospect of engaging researchers or drug companies to work on finding a treatment?

Sanath Kumar Ramesh: Initially when we got started, we thought we were going to face an uphill battle because there are so few patients with this disease that nobody would really care. But fortunately for us, this gene has been in the center of some cancer therapeutics recently. Although it’s not as popular of a gene for cancer as some other genes are, some researchers have been studying this gene as a potential target to suppress for cancer. For my son’s condition the need is not to suppress the gene, but to do the opposite and express the gene more. We’ve been able to get a few researchers excited and get some research work started. I think the real challenge is that when I approached biotech companies about this work it was obvious that all the companies wanted to help but their business model did not allow them to because there is no direct return on investment. So, I’ve gotten a lot of support from biotech companies in terms of them lending their expertise, guidance, and making connections. But at the end of the day, I’m looking at all the work that I’m doing for my son and asking myself, what happens if another kid is born with this disease five years from now, who is going to make treatments available for these kids? Unfortunately, the answer is no one. Someone would probably have to redo all the work.

Daniel Levine: You and I have spoken before and I think anyone who looks at what you’ve accomplished in a short of amount of time would be astounded. There was this moment of realization for you, that you were not alone in the case of having a child with a rare condition with next to no prospects of a drug company being able to pursue it. When did you realize a common need among people with thousands of other rare diseases?

Sanath Kumar Ramesh: I started working on Raghav’s gene therapy for his specific condition. Gene therapy made the problem clearer because of the cost that it takes to build a gene therapy treatment. A drug repurposing experiment would cost somewhere between $100,000 to $200,000. That is in the realm of possibilities for a patient or a patient family to fundraise from friends and family on GoFundMe or Facebook. When it comes to gene therapy, we are talking about $5 million to $7 million dollars. There are some patients that have defied the odds and raised this money. To me, it’s a tradeoff between how much time I want to spend on fundraising versus how much time I want to spend on my son. So, I started talking to a lot of biotech companies about whether they would be interested in funding this disease. Obviously, the answer was: I would love to but unfortunately my hands are tied. Then, I started talking to other patient foundations, especially the ones that have more prevalent or incidence populations, that have a hundred, or five hundred, or a thousand patients. When I started talking to them, I identify two cohorts. In the first cohort, there were patients that had made exceptional progress and did raise the millions, got a gene therapy program in the clinic, and even got a few patients dosed. Unfortunately, when they went back to the biotech companies to hand off this program, there were still challenges in the company’s ability to take over the program. The challenges would be either the experiments were not done right, the right vector was not used, or this was not going to fit in with the platform technology that the company was focused on. So, regardless of all the money in the world that they put in, this technology is sitting on someone’s shelf without getting to patients. The second cohort is where they had 500 patients worldwide, but there was no unifying voice, no driving force behind it. They had some basic animal models built, but they had not gotten the research studies started, even though theoretically looking at their gene and their disease, gene therapy would be a good fit for them. After seeing these two cohorts of patient foundations, it was clear to me that the noise that we are hearing from the industry around SMA getting treatments, progeria getting treatments, and so many other rare diseases, is awesome and motivating, but there are thousands of diseases that are never going to make it beyond the cut line unless we do something about it.

Daniel Levine: What is Open Treatments and what will it enable patients to do?

Sanath Kumar Ramesh: After I found out that there are still diseases that are never going to be commercially viable, I started asking myself the question, what can we do about it? I started talking to a lot of researchers, academic researchers specifically, because I knew that the answer lay in academia. Since we are pushing the frontier and getting new technologies out the door, the answer has to be in academia. The more I started speaking to academic researchers, it was obvious that the technology we need for a lot of these diseases already exists and has existed for decades now. I am talking about AAV gene therapy technologies. The challenge really is in manufacturing and driving down the cost of manufacturing. There are many initiatives now that are pushing that boundary forward. I asked myself the question, if the technology became cheap enough, how likely are these diseases to become commercially viable and be able to be taken into the clinic? The answer unfortunately is that it’s unlikely because the diseases are still going to have a lot of risks. The risks are a lack of animal models, lack of understanding of the disease, lack of natural history, and lack of patient registry. All these risks are not going to be solved by a company investing money because they want to invest after the risks are solved, and not before. Academia is not going to be investing in these risks because it is not going to lead to a paper and so it does not follow their incentive model either. Now the third group that could potentially invest would be governments. It’s going to take years before the government is going to invest in any of these diseases. I hope they do, but it’s not on the horizon for anybody in the next couple of years. I wanted to somehow connect people who are capable or interested in solving these diseases or de-risking them. That is the goal of the software platform that I’m building called Open Treatments as a part of the Open Treatment nonprofit organization. The software platform is focused on decentralizing drug development by providing patients, patient families, and patient-led organizations the right roadmap, people, and infrastructure to execute their drug development program. Our focus now is on gene therapy in the beginning, but I’m fairly certain we will expand to other therapeutic technologies in the future.

Daniel Levine: What problem does this solve for patients and their families?

Sanath Kumar Ramesh: So, both patients and their families have a lot of motivation and drive, just like I have to help my son. Unfortunately, it takes an enormous amount of time before you actually become an expert, first in the biology, second in the disease, third in the drug development technology, fourth in regulations, and fifth in the entire process of connecting all of these together. Even if you can be an expert in one or the other, it’s not sufficient. You have to be an expert in all if you want to act like a well-oiled machine, like a biotech company, and deliver results in the clinic. The problem I’m trying to solve with Open Treatments is now that patient foundations have gotten savvy enough to bring in the scientific experts that have deep understanding in the gene and the biology, can we supplement that with process expertise and tools so they can operate like the well-oiled machinery that I’m talking about. So, Open Treatments provides a software platform. Think of it as a project management solution. The software platform will give you a clear roadmap to build a gene therapy product starting from scratch. You can build your animal models, your natural history studies, your construct design, plasmid creation, and all the stuff up to manufacturing or dosing your patients. Through the Open Treatments platform, you can connect with the right service providers to execute these activities for you. We also supplement the software platform with expert advice from people who are experts in the drug development process, they are not necessarily experts in the disease area and that’s fine because it’s supposed to be complimentary to what the foundation’s current expertise already is. Together we hope that foundations will be able to run like a very small biotech and get drugs into the clinic faster. My strategy is to cut the time to decision-making. So, if a foundation is spending months trying to decide whether to build a knock-in mouse or knock-out mouse, and we can cut the time in decision-making from months to weeks or days. That is a drug that will emerge in the clinic faster.

Daniel Levine: You mentioned you’re initially focusing on gene therapies. How expansive are you using that term?

Sanath Kumar Ramesh: Actually, I am focused on gene replacement therapy. I’m focused on our ability to use AAV-based gene replacement therapy and deliver them to any part of the body. I’m focusing on AAV-based because there are differences in the roadmap when you use a different type of vector. I am not specifically focused on a CNS disease or a muscular disease as long as we can find the right vector available in the market for us to continue the program. I am also focused on diseases that are amenable to gene replacement therapy using AAV. Specifically, what I mean by that is over expression of your gene should not be harmful and your protein should have less than 1,100 amino acids that can fit within an AAV. So as long as we can get this requirement satisfied, I think Open Treatments would be a great platform for a disease to build on top of.

Daniel Levine: Might you expand this to gene editing and ASOs down the road?

Sanath Kumar Ramesh: That’s the plan. What I really want to do is start with gene replacement therapy and understand the process challenges that foundations go through. Right now, the challenge that we have so far in building this platform is that we expect a very high level of understanding and scientific knowledge from the patient organizations. We don’t hand-hold on what a mutation is or what a gene is. We expect that level of understanding to be present. We also expect the patient organization has an understanding of the risk they are taking on. When I got started on this journey, I did not know that I was taking a risk when I stepped on a drug development platform. The risk could be that your drug might not work, or the risk could be that you give it to a patient and there might be adverse effects and none of the risks could be predicted beforehand. The risks can be remediated in some form or fashion, but they can never be predicted. I don’t want to give hope to patients and patient families upfront and take it back from them later when they understand the real risk that they’re taking with a drug development platform. So, I am in the process of starting with gene replacement therapy and a very small set of patient foundations. That way we can clearly understand what the requirement from them is, in terms of their ability to execute and build guard rails in the platform, so others that are following suit will not fall into traps. We are starting with a limited set of technologies and a limited set of diseases, but then we will expand to ASOs, gene editing, drug repurposing, and whatnot.

Daniel Levine: There’ve been a number of efforts to enable people to pursue bespoke therapies. Do you see Open Treatments working with these efforts in any way, or do you think there’ll be some synergies between them?

Sanath Kumar Ramesh: A lot of these efforts have been focused on a later stage therapy development. For example, there is the bespoke gene therapy consortium from the NIH foundation. They’re doing amazing work focused on reducing the cost of manufacturing and making it cookie-cutter to take a program into a clinic, but they are not focused on diseases that don’t have their basic infrastructure built. There are other bespoke therapy development efforts, and the n-Lorem foundation, who are doing amazing work in ASOs, but their focus is to make sure that the basics are already there before they take over these programs. I’m sure there’s going to be a lot more of these bespoke gene therapy efforts coming down the pipeline, but my focus with Open Treatments is on the early stages. As soon as you get a diagnosis and a disease is discovered, how soon can we get this disease de-risked to a point where these other bespoke therapy development efforts can take over? So, think of Open Treatments as the first leg of a relay race.

Daniel Levine: Where is Open Treatments in terms of development? What more needs to be done?

Sanath Kumar Ramesh: Great question. We just incorporated our foundation with our board of directors last month. We have Ethan Perlstein, Julia Vitarello, and Plavi Mittal, who are our board of directors. We are just starting to get some customers onboarded to our foundation. In parallel, we are pursuing our open-source software development. What I mean by that is, all the source code of the software that customers will be using, in this case patient foundations, will be open source and available freely for anybody to use under a specific Linux Foundation project called RareCamp. The open-source development process is a long process, but it’s one that has the ability to scale around the world. My vision is that we can do the software development and give it as a gift to the community for the long term and we can bring in software developers from around the world to contribute to building the software platform. We are in the process of finishing our first release and launching by the first week of April. That’s when we will onboard a very limited set of patient foundations onto the platform, three to five would probably be the magic number at launch. We will continue the software development process in parallel and add more and more capabilities. We are sort of taking the Silicon Valley approach of “move fast and break things.”

Daniel Levine: One of the things you’re doing is building a marketplace of sorts for patients and patient groups moving along the therapeutic development pathway to not only understand what steps they need to take, but to connect them with service providers to execute those steps. What’s the range of service providers you’re seeking to build into the system and who are some of the folks you’re working with?

Sanath Kumar Ramesh: This is a marketplace, but a different type of marketplace where we are not interested in listing every service provider like Yelp; instead, we are interested in identifying the best service providers to work for each of the steps in the process. For example, we have partnered with Castle IRB to help if you want to get a fibroblast study done or if you want to start a natural history study; we are collaborating with Odylia Therapeutics to help us with expert advice for the gene therapy development process; and we are in conversations with several other providers as well. Our vision is that we will have at least one provider per step. One provider for building mouse models, one for constructing vectors and plasmids, one for manufacturing, and so on. In the beginning, in the next three or four months, we will be understanding what the patient organizations’ needs are and then expand and change beyond that. We do have a lot more collaborators that have helped us build this platform. For example, GlobalGenes has graciously donated some of their time in helping us build some of the education materials, Charles River labs is also collaborating with us in providing scientific advice and expertise, and I’m also working with the Linux Foundation, which is providing advice and expertise in the open-source development process. So, there’s a lot of folks that are helping us build a platform, and there will be service providers that will be available for the patient foundations to use as well.

Daniel Levine: Obviously it’s early days, but have you gotten any response from the patient community so far?

Sanath Kumar Ramesh: Yeah, a lot of positive responses. I think one of the best responses that I have gotten was a patient foundation that told me that this platform could take them from walking on the sidewalk to cruising at a hundred miles per hour on the freeway in a few minutes. That is a visual that keeps coming back to me again and again because walking takes a long time to get to your destination, but a freeway can get you there faster. At the same time, you have to be careful, there are more risks in driving a hundred miles an hour on a freeway than walking. This is why I am starting slow and expanding as we go along. We will have three to five patient foundations onboard on the platform and one of them will be my son’s gene therapy, because this is where my whole journey started. I like the process of learning through my son’s gene therapy and continuing to add feedback to Open Treatments. Another foundation is IDefine, which is tackling Kleefstra Syndrome, and they will onboard onto the platform in April; and Cure CMD, which is an umbrella organization taking care of several continental muscular dystrophy conditions and we will also be onboarding a couple of their programs onto the platform.

Daniel Levine: My next question was whether GPX4 was one of the targets for this; where are you in development and how is your son doing?

Sanath Kumar Ramesh: It is always going to be the target for it. I am my own customer at this point. So, if something works for me, I’m fairly certain it will work for other people. We are in the process of verifying the construct design. We have five or six types of constructs that we have designed for the gene therapy. We are in the process of verifying which of these work the best in a cellular model. Once we have some confidence in the data, we will scale it up to a proof-of-concept study and then to manufacturing, Raghav is stable overall. Stable is always good for us because of all the challenges that he’s having. A day where he’s stable and smiling and happy is the best day for us and that’s definitely been the case for the last few weeks.

Daniel Levine: Sanath Kumar Ramesh, founder and CEO of Open Treatments Foundation. Sanath thanks so much for your time today. Thank you.

Sanath Kumar Ramesh: Thank you so much for having me here. It’s such a pleasure.

Thanks to Pfizer, Inc., Bluebird, and Novartis Gene Therapies for their support of this podcast, part of our Platforms of Hope: Advances in Gene Therapy and Gene Editing series.