S3, E01: A Synergistic Approach to Treating Huntington’s Disease
About this Episode
Huntington’s disease may only affect one in every 10,000 people in the United States, but its symptoms can drastically debilitate a person’s quality of life.
For Ignacio Muñoz-Sanjuan, he witnessed first-hand the devastating effects this disease can have. He’s visited parts of the world that have the highest prevalence of Huntington’s disease on the planet, including Taiwan and South America. Today, he’s involved with two different nonprofit organizations seeking to accelerate the development of treatments to help those afflicted by, or at risk for, this fatal condition.
Join us as we explore Ignacio Muñoz-Sanjuan’s journey in raising awareness about Huntington’s disease, how Charles River Laboratories contributed to developing a framework for potential treatments, and what he believes the future holds for drug development in this disease area.
Ignacio Muñoz-Sanjuan (00:01):
But as I was told once in Brazil by a person who was in advanced stages of Huntington's which also influenced my thinking a lot. He told me, "I know it's too late for me, but please keep up your work and help my daughter." And I keep that in mind every day.
Chris Garcia (00:26):
Huntington's is a rare inheritable condition with no known cure. One of its most distinct features is that patients don't typically begin experiencing symptoms, which affect their motor, behavioral and cognitive functions until middle age. This greatly affects their ability to work as well as their quality of life. Imagine you're in your early sixties and have progressed to the later stages of this debilitating disease. Only, you also live in an economically depressed region where healthcare access is limited, disability payments are not available, and your caregiver, who is your daughter, is beginning to experience symptoms herself. I'm Chris Garcia and in this episode of Vital Signs, Gina Mullane speaks with Ignacio Muñoz-Sanjuan, a scientist who has dedicated his life to Huntington's patients. Both through his drug discovery work and its humanitarian efforts in Latin America. We'll discuss the struggles faced by Huntington's patients and vulnerable communities, the unique challenges of developing novel therapeutics for Huntington's, and the important legacy today's science may have in curing this transgenerational disease.
Gina Mullane (01:27):
Ignacio, I want to thank you for taking the time to speak with us today. I'm told you like to be called Nacho, is that right?
Okay, I like it. That's a great name. So tell me about CHDI. What is the foundation that you work with?
So, CHDI foundation, its a non-profit organization that was funded many years ago, probably two decades ago to try to accelerate or develop treatments for Huntington's disease exclusively.
CHDI plays a critical role for Huntington's research. Rather than focusing solely on academic research as many foundations do, CHDI's mission is to bridge the gap between academic and industrial research. Their goal is to develop therapeutics to the point that pharmaceutical companies will be willing to take them on for full clinical development. As a non-profit, CHDI's bottom line is the time to market for life-saving therapeutics. To this end, they collaborate with researchers rather than competing with them. The organization's scientific team offers their partners domain knowledge, reagents, protocols, animal models, and funding so they can work together toward their common mission, to provide clinical relief to the Huntington's patients as quickly as possible. Let's hear from Nacho on the drug discovery work he's been leading as CHDI's vice-president of biology.
When I started, I was the only biologist, vice president in charge of all of the translational programs so regardless of topic I worked very closely with the Vice President of Chemistry Celia Dominguez to both build the drug discovery infrastructure as well as being in charge of all of the biology support for all of their drug discovery programs. More recently in the last six or seven years the field has expanded. I assumed a more restrictive role driving the Huntington lowering therapeutic programs as well as any neuroscience symptomatic treatment approaches at CHDI.
It sounds like a tremendous amount of work has been put into developing your drug discovery program. You mentioned CHDI's program is focused on targeting the Huntington gene. Can you tell us more about the progress you've made and the challenges you've faced in developing novel gene therapies?
I think the history of drug discovery is very complicated as people know but if they don't, they should know that neuroscience drug discovery is a very low success rate exercise so success is defined in many different ways, I think that the most successful thing that CHDI has done is to really generate a framework by which anyone can develop drugs for Huntington's. I think in terms of individual drug discovery programs there are several that come to mind. The first one is the gene therapy or molecular therapies that we've developed including, in collaborations with Sangamo Therapeutics for a program that selectively targets the mutant Huntington allele with a gene therapy approach that is in late stage preclinical development that so far is the only allele-selective therapy that would work on every individual assuming that when it goes to the clinic or if it goes to the clinic that it would work.
Second thing I'm very proud of is the fact that we developed from [Sera 00:05:08] a set of novel imaging, small molecule binders of Huntington that can be used for PET and this is very important work because it enables an understanding of where the gene therapy agents are acting in the brain, so all of these programs I'm very proud of because they've delivered critical tools for drugs that within can have a profound effect in how we do trials and interventions. There's been many other programs that I'm very proud of in terms of the drug discovery work that we did.
For example, histone deacetylase inhibitors or kynurenine monooxygenase inhibitors. I think the problem there was not the work that we did but rather that the biology did not pan out in the way that we thought when we started the work based on academic publications meaning once we develop a drug that is suitable as a therapeutic. The interventionist studies in preclinical SPCs did not support additional investment in terms of clinical development so there's a lot of programs that I could have mentioned here that unfortunately were abandoned or deprioritized simply because the data in the preclinical SPCs did not support going into the clinic with those molecules.
Another hurdle in developing Huntington's treatment is, simply expertise. In order to effectively manage clinical trials, researchers must have multiple clinical sites, know how to standardize how clinical trials are conducted across sites, and be equipped to interact with regulatory authorities and in order to get to this point, they must first have a full understanding of the biology of the disease, animal models that enable drug discovery, and programs that hold promise for clinical development. A tall order when it comes to a condition as rare and complex as Huntington's.
It sounds like your preclinical work has been fulfilling but not without its challenges, so what type of programs have you partnered with Charles River on?
Lots so, in fact the first meeting that I had at CHDI was with Charles River in Liden. This is almost 13 years ago, would be I think it was in January 2008 and we had a meeting to discuss a genomic screen that was being done out of the Liden group before it became part of the Charles River Infrastructure, so as people probably know, Charles River is a company that has expanded a lot over the years both in terms of the number of companies that it acquired, as well as in the breadth of services that it provides. For example, the histone deacetylase inhibitor program class II, it's four inhibitors were done in Charles River. A lot of the work that we've been doing on a novel oral drug that lowers Huntington systemically throughout the body, the novelist place and mechanism has been run out of Charles River. There's just a lot of different programs.
We love to hear directly from longtime partners like Nacho, who have benefited from Charles Rivers' strategic expansion over the years. We are proud to have collaborated with CHDI through multiple stages of their preclinical work, from early target identification and drug discovery in our labs, to later stage in vivo studies at our site in Finland.
From the very beginning, he was one of the two main CROs that we've collaborated with and we've run many different programs so I've been working with them for 13 years. Anything from genomic screens and target identification projects, to drug discovery programs that were very well run.
So, let's talk a little bit about the outcomes of the work that is being done on Huntington's and how that translates into the patients and it's the reason we wake up in the morning, right? And why we do what we're doing and so I was wondering if you could take us into what this disease, Huntington's disease, what it means to patients from a financial impact, from a lifestyle, what is it like and what are the drivers to help improve that?
Well, I think Huntington's disease is an extremely complicated disease and I think there are two major components that make it so. The first one is that it's obviously a mental disease that affects people in the most productive years of their lives so in contrast, with most forms of neurodegenerative disorders of the brain like Alzheimer's or Parkinson's, Huntington's affects people in the third or the fourth decade of life. By that time people have careers and they have families, probably have a few kids depending on where they live and they become unable to work within a few years of being diagnosed with the clinical stages of Huntington's and the disease progresses very slowly which requires essentially continuous care over at least a decade of their lives. That puts an extraordinary burden on the families, both on the caregiver but also economically because the person who develops the symptoms can't work in their prime years.
In many cases, they don't have disability benefits in many countries of the world and then the burden for the caregiver means that another person in the family is going to have to be taking care of the affected individual for a decade or more so you're eventually losing two salaries in the family.
The second component that exacerbates all of this is the genetic aspect of it and Huntington's is very unusual in that sense that it's a genetically dominant disease. 100% of people have mutations in a single gene and on average, 50% of the kids born to an affected parent or the person that carries the mutation will develop the disease so you can imagine if you have a family, an extensive family, your siblings, 50% of them will be affected. Your kids and their kids, 50% of them will be affected.
So, over several generations of living with Huntington's disease, families get progressively condemned to poverty and part of the reason for that is that people that are traditionally in the best position to help an affected person being your parents, your siblings, or your children, might also be affected by Huntington's disease in the nuclear families so a lot of the traditional support is lost and certainly financially, the family at large, very hard hit by the disease and this just perpetuates over time so it's a combination of those two factors that makes this a real terrible disease that has impacts way beyond the symptoms of an individual.
And I know that you have spent a considerable amount of time and effort to work on helping people to fight this disease, not only in the lab but in your personal life and I was wondering if you could tell us a little bit about the work that you've been doing to help families and provide a better life where possible.
Yeah, so let me take you back maybe 15 years or 14 years. I think soon enough that I started at CHDI I gave a talk in Taiwan and the organizers of the conference asked me what I wanted to do, if I wanted to do sightseeing and I said no, I'd rather go to the hospital to meet some of the HD families in Taiwan and I met a couple of families but one thing really struck me and that was, I met with a teenage kid, we have a translator and his father was in a terminal stage in the hospital and his younger sibling was three and was already suffering from Huntington's disease and he was probably in his 16, 17 years of age and with a translator I was asking him how much he knew about the disease.
And if he knew anybody else that that had Huntington's and he said no, he didn't know much and he didn't know anybody and I said, "do you have anybody to talk to?" And he said, "no." So at that moment it made me realize that is such a shame and a stigma associated with a mental genetic disease and this kid was clearly afraid of developing Huntington's himself but had nobody to talk to. So I decided at that point to start writing a blog about the science of Huntington's as a way that maybe educating people that turn into really wanting to learn more about the daily experiences of people living in Huntington's families and soon after that, I went to South America to try to establish a network of clinicians and scientists similar to what we do in Europe and the US.
And I also gave another seminar there and at the end of the seminar, a set of mostly women who run family associations in different countries approach me and they were telling me how little support they were receiving. So I decided to spend a couple of years during my holiday time traveling through south America. I went to Brazil, I went to Venezuela and I went to Columbia and I went to these places because this is countries where there are regions or towns with the highest prevalence of Huntington's in the world and in fact, in Venezuela, there are several towns with an incidence of the disease that is probably a thousand times higher than in the general population and this is part of the reason why this populations would have studied for about 20 years and that led to the identification of the gene that causes Huntington's disease.
And during the course of visiting these places I have realized that we had a real humanitarian crisis unfolding or established in this communities around people living in extraordinarily vulnerable conditions. People dying on the streets, people are starving to death, people with no access to any medical care, thousands of children at risk that were living on the streets because parents had died from Huntington's disease and they had no support. So I decided at that point that I needed to do something today to try to help them out and that something was something from the perspective of a social humanitarian aspect and that's how Factor-H was born and Factor-H eventually developed into another non-profit humanitarian organization that I funded and I currently lead as a second job from my main scientific job.
Factor-H began with the spark of Nacho's idea nearly a decade ago. But since then, its mission has garnered mounting support from the Huntington's community. Founded in 2012 by Nacho and his colleague, Dr. Claudia Perandones, Factor-H was established as a formal non-profit organization in 2018. It has brought together people from a range of professions, countries, and worldviews and its mission to improve the future of communities in Latin America most effected by Huntington's. What began as a passion project is today a successful platform for programs and health and disease management, youth engagement, community development, and data collection, and advocacy. All making a tangible difference for the most vulnerable of Huntington's patients.
I love the vision for Factor-H. A world in which families and communities impacted by Huntington's disease live in dignity, equality, and prosperity. Exercising their basic rights including their right to health and education. It's really powerful and the story you just told really speaks to that. Can you tell us a little bit more about progress on that vision and what's on the horizon?
Well, when I started doing this I even had conversations with some people who were very skeptical that whatever I would do would make any difference and my philosophy has always been, I think both in science and in life is that when to step forward one day at a time and just take it slow but steady and helping one person is better than helping no people and helping two is better than helping one so I'm aware that with the limited resources that we have, we're not going to be able to solve every problem and help every person with Huntington's disease but we can, at a minimum change the conversation and significantly impact a few people in those communities. So I think we've made very significant progress. The first one I would say is by raising awareness.
And I think the fact that we're having this conversation is already a sign that we've been successful in that sense. Second thing is our philosophy for working in those communities has been to work through them. So Factor-H is really a catalyst, an advisor, a resource, a set of tools for the local communities to improve their quality of life so we work with local universities to provide medical support, to provide psychological support, to provide educational support and that's true in Colombia and Venezuela. So all of the work that we do is managed by people in those countries. Mostly alliances through universities and other non-profits that have the expertise that know the system, know their political system, know what to do and what not to do and effectively liaise with the local communities. You have to understand, particularly in Venezuela but also in Columbia and Peru, a lot of these communities would have studied over many years by people who came in, took a lot of samples, studied them, and they uniformly feel that they didn't get the change that they were hoping for.
As a scientist, Nacho has felt the highs and lows that come with the business of drug development. One day you can make a breakthrough in the lab and much later, sometimes after months of testing, you face the realization that your therapy will never make it to market. The effects of this are felt even more deeply by patients who are involved in Huntington's research and clinical trials. As drug developers, it is our obligation to balance hope and expectations with patients and to help them understand that everything they do is contributing to a treatment being found if not today, then someday. Without a fundamental trust between researchers and patients, therapeutics stand a little chance of being brought to market. Nacho shared with us how he aims to build that trust in the communities he visits.
So when I first started going there especially as a scientist, people were very skeptic that my intentions were just to help them. So part of the things that I did initially was going back regularly every six months or sooner, I would go back, I will give a talk, I will meet with them informally until I earn their trust and I tried to engage local agents, particularly youth to essentially be the main tool to engage the community effectively. We also fund the people that are working in the local family associations in each one of the countries and it's almost irrelevant whether the Factor-H is recognized or not as an agent of change there.
Our mission is to bring assistance to them and educate them about the disease, how to treat people and also we put a lot of effort on the next generation of kids and youth at risk for Huntington's so they can grow up with better psychological and practical tools to have a more productive life. So we work at different levels and over the years we've changed our approach to be a rights-based organization, the right to health, the right to education, the right to food, the right to adequate housing and the right to live a life full of opportunities and that's the mission that we're striving for and we've made significant strides in that way but there is still a lot to do.
It's such a labor of love for you. I can hear the passion coming through that you have for this cause and the people and it's incredible the amount of impact that you're making. As somebody who's actually day to day working in the science and then translating it into the human humanitarian side of it, do you ever feel like the parallels are set up perfectly for you or do you have a hard time balancing where you spend your time and energy?
I don't I have a hard time balancing my time I mean we all do in some ways but we've grown a lot and we know we have a staff on the ground and the staff here in the US now so they've taken a lot of the burden that I used to do on my own.
And what has Nacho done with the time that's been freed up? He's put it right back into the Huntington's community. He begins his days with CHDI early and dedicates evenings and weekends to his work with Factor-H. This could be too much for some but as Nacho explains, the two sides of his professional life create a synergy that keeps him going on his toughest days.
So interacting directly with people affected with Huntington's, particularly living in very difficult situations and seeing a lot of people die, whether it is from the disease or suicide which has happened many times during this last 10 years. There's nothing more to motivating to your scientific work than seeing that these people need you and need the output of the work that we're collectively doing. So I find that stimulating in moments of despair as we all experience what we're doing in science works. Science takes a long time. You have to put that in perspective and I think the work that I do at Factor-H tapers that tendency to despair in terms of how slow things are and how frustrating science can be.
On the other hand, my interactions with people and the ability to fundraise and the ability to have some credibility about the humanitarian work also is influenced by the fact that I'm a scientist leading programs in Huntington's and particularly patient communities care about what's going on in research and I'm a conduit to try to communicate to them where we are, where we're headed and try to engage local scientists and clinicians in each one of these countries to work more actively to help their own communities and I'm under no illusions that if I didn't work in the field of Huntington's disease, I wouldn't have those connections so I think the play, they help each other.
Yeah, I love that framework of the synergy and I imagine as a scientist, being that close to the patients and seeing the needs that they have really underscores the work that you do and motivates you every day. What do you see for the future, for research and drug development for Huntington's disease? What is your hope?
Well, my hope is that we find treatments that at least work on some symptoms if not delay the progression of the disease. I mean, we've had a tough year, the most funds programs were stopped but the rose and the wave programs, we still have some Huntington lowering therapists in the clinic. Unique cures, gene therapy approach is surviving and doing well so far and we have a set of oral drugs that are coming up which have novel drugs developed by Novartis PTC Therapeutics and Skyhawk and I'm hoping that at least one if not more of those will eventually reach the approval stage and those drugs will have meaningful clinical impact. I'm also hopeful that the more work we do through Factor-H, the more of an international awareness is taking shape that treating Huntington's is not just about medication.
And it really requires different sectors of professionals working together. Social workers, psychologists, educational specialists for children that are for example, living in each of the families. People who specialize like occupational therapists and giving families with HD the tools to be financially solvent and clinicians coming together and I think this is something that we're trying to do through Factor-H so we organize conferences where we bring together all of these people and spend a week together living and doing activities together and I think the more that we can bring these different sectors of the problem together, I think the more that we can potentially help those individuals affected with HD so I'm hopeful for the future. I'm also aware that this is probably a transgenerational problem. I suspect that a lot of people that I know today with Huntington's disease will die with Huntington's disease.
I don't think the advances that we're making may have reached them and I think we all need to realize that we want to make a difference. The difference may not come in our lifetime but it will come in the future and the work that we're doing today is critically important for that day. It's like climate change, right?
It may not affect us, it will affect our future generations but the time to act is now and I see our work in Huntington's very much in the same light. In 2017, we had an audience at the Vatican with Pope Francis. There is a documentary called Dancing at the Vatican available for free on YouTube. I was the casting director and they chose the families that represented both Colombia, Venezuela, and Argentina to meet the Pope and after that event a group of young, at risk people in one of the two most effective towns in Venezuela decided to form their own youth organization to take action for their own community.
So, that's a tangible impact that we already had through the interaction with youth in those communities. The second thing is we have a sponsorship program for children between the ages of three and 15. This is the sixth year that we've been doing it in Columbia. We have about 150 children that we've been sponsoring within Colombia and Venezuela. We're expanding that program which is now called New Horizons to cover at least 300 kids. The consequence of bringing kids together from different families in the future hopefully different countries, all at risk, all living in very similar precarious situations in terms of poverty and in terms of living with the disease has created already a community of kids who've grown up together, understanding they come from Huntington's family, understanding how to interpret their parents' situation, disease and with a circle that is more supportive of themselves.
Remember when I mentioned the kid in Taiwan, I didn't want to have a child who grew up in fear not having anybody to talk to and that's the origins of this program and I think we've made very significant strides in having kids grow up with more information, more resources, and more hopeful about their lives and I hope to continue to expand this program, to reach every kid at risk for Huntington's in the countries that we work in.
Well, thank you so much Nacho for sharing that, that was a really inspirational story and I'm inspired by your words and your work.
And it really pushes us to all step up a little bit more so thank you so much for sharing today.
Yeah, I just wanted to say anybody who's listening, if you're from Charles river, thank you very much for all the work that you do. It's very important to us and to the patient community. I think if you just have an interest in Huntington's or you have an interest in asking yourself how you can help the communities that would represent Factor-H are people that need people like you and thank you so much and thanks again for the time to showcase this problem.
Ignacio Muñoz-Sanjuan is vice-president of biology at the CHDI foundation and president and founder of Factor-H. Please check out our show notes for more information or go to Factor-H.org, that's Factor dash H.org. If you have questions about anything you heard today, please send them our way @vitalscienceatcrl.com. Join us next month as we continue our exploration of emerging curative gene therapies that transform the lives of patients. Until next time, thanks for listening.
- Huntington’s Disease (HD) Studies
- DNA Damage Repair and Huntington’s Disease
- Factor-H South America
- Dancing at the Vatican
- Ignacio Muñoz-Sanjuan Speaks About Factor-H
- Accelarating Therapies for Huntington’s Disease
- Factor-H, Strengthening Communities Afflicted by HD in Latin America
Hosted by: Gina Mullane
Narrated by: Chris Garcia
Special thanks to: Ignacio Muñoz-Sanjuan
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