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What We Owe Terry Horgan: Reflections from Providers, Family, and Scientists

2023; Mary Ann Liebert, Inc.; Volume: 34; Issue: 19-20 Linguagem: Inglês

10.1089/hum.2023.29247.editorial

1557-7422

CRISPR and Genetic Engineering

Human Gene TherapyAhead of Print Free AccessWhat We Owe Terry Horgan: Reflections from Providers, Family, and ScientistsPublished Online:12 Oct 2023https://doi.org/10.1089/hum.2023.29247.editorialAboutSectionsPDF/EPUB Permissions & CitationsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail I first saw Terry Horgan as a patient. I was filling in as the pediatric pulmonary specialist in the UMass-Duchenne Muscular Dystrophy (DMD) center, an excellent multidisciplinary clinic exclusively for DMD patients that is run by Dr. Brenda Wong. My role on this one visit was to evaluate every patient's respiratory status and make recommendations for their care. During that visit I also met Terry's brother and his mother. I learned that Terry's brother, Richard Horgan, was working to create a gene therapy for Terry. In my research career as a gene therapy scientist, I knew that several DMD gene therapies were in the pipeline, but DMD was not a disease that my own laboratory had worked on, so I had only followed that work from distance. After making my pulmonary recommendations, I wished them all well, and did not see them again for some time.Years later, Dr. Wong contacted me to tell me that she wanted to treat Terry with an innovative “bespoke” gene therapy, one designed just for his own personal mutation. This approach was chosen because Terry, at age 27, was too old for any of the proprietary gene therapies that were in clinical trials. I gave Dr. Wong and her team advice from time to time but was not deeply involved with the case until September 2022, after the therapy had been manufactured. In the weeks before Terry's therapy was given, I became more involved, providing my own insights on preventing immune complications in his case. Our concerns about such risks were amplified in his case because Terry's age and stage of disease gave him less physiological reserves to deal with adverse effects from the therapy. After suggesting as many safeguards as I could think of, I also made sure to be a part of the informed consent process with Terry and his family. I wanted to make sure that he was fully informed of the risks.The rest of the story is, unfortunately, familiar to many in the field. Terry received the gene therapy, but began experiencing cardiac complications in the first few days afterward. As his condition gradually worsened, multiple additional doses of immune-suppressive, anti-inflammatory, anti-cytokine, and anti-complement therapies were given. Despite intensive care unit support, mechanical ventilation, and extracorporeal membrane oxygenation at UMass and Boston Children's hospitals, Terry died. A limited autopsy was done at Boston Children's hospital, which showed that Terry had suffered from adult respiratory distress syndrome most likely as part of a “cytokine storm” that the vector had triggered. This process had caused his lungs to fill with fluid and had put stress on his heart that it simply could not take.After Terry passed, there was flurry of commentary among scientists and in the press. Various parties sought to use Terry's case a “talking point” in an argument about the risks of gene therapy or of CRISPR-based therapies or of some other aspect of the clinical trial process in the United States. Some drew parallels to Jesse Gelsinger, a young man whose death in one of the earliest recombinant adenovirus gene therapies has been viewed as a trigger for the decline in support for gene therapy in the early 2000s.In my view, it is deeply wrong to turn the suffering endured by Terry Horgan and his family into a punch line. Terry was, in fact, a bright and courageous man who understood that he as taking a serious risk with his life by undergoing this experimental therapy. Terry understood that he might die from side effects of the therapy. Yet, I never once heard him waver from his resolve to try it. He made it very clear that he wanted to do this whether it helped him personally or not. He recognized that there were no therapies available that were going to help DMD patients in their 20s. He was determined to “rage, rage, against the dying of the light.” He and his family wanted the therapy to work for Terry, but at the very least they were bravely resolved to have his participation in this trial provide data to inform future trials for other DMD patients who currently have no good options.Since Terry's passing, I have also reflected on all these events. Although Terry never expressed regrets, I deeply regret that the therapy did not work for him. I regret that neither I, nor any other member of the team, was smart enough to prevent or reverse the terrible consequences that ensued. But along with that regret, I also owe Terry many things. I owe it to him to get every possible bit of data from his case published and disseminated to all gene therapy scientists working in this field. I owe it to him to do my part in scientific discussions of how to overcome obstacles preventing older DMD patients from gaining the benefits of gene therapy. I owe it him to speak out on behalf of patients who are being left behind as gene therapy advances, because they are too old or too sick or have a disease that is too rare to make for a neat and easy gene therapy success story.In this field, we have a moral obligation to make gene therapies accessible to all, regardless of disease rarity, financial circumstance, or geographic location. I owe it to him to remind myself and my colleagues that our patients are people, not just experimental subjects. We have been granted the privilege to access their outcomes as data to inform the science of gene therapy, but we owe it to them to respect the fact that they are each unique persons with thoughts, hopes, and dreams for the future. Patients should never be used as punch lines. In the end, Terry Horgan was not a victim, he was a warrior. We should all recognize that fact and respect him for it.Terry Flotte, MDUniversity of Massachusetts Chan Medical SchoolIt was inevitable, some might say even destiny that our paths would cross with Rich Horgan and Cure Rare Disease. Similar to Rich, we have shaped our lives around advancing research and finding treatments for muscular dystrophy. Monkol's diagnosis with limb-girdle (LGMD2G/R7) in his 20s served as an awakening to our life's mission. In navigating through the world of rare genetic diseases, it was not uncommon that we encountered patients such as Terry Horgan, who wake up each day with the mental burden of a lethal condition. However, what made our encounter with Rich different at the time was that we had reached a stage of our lives where we could take proactive steps to give Terry, a Cornell graduate and productive member of society, a fighting chance to maintain quality of life.We had just moved to Yale University and set up a research laboratory, where we could dedicate resources and hard-working hands to come up with a personalized strategy to address Terry's condition. Although several gene therapy clinical trials were underway for DMD, Terry's unique mutation and age excluded him from these trials. Inspired to help Terry, we devised a therapeutic strategy using CRISPR activation technology, and showed proof of concept relatively quickly—first in cells grown in a dish, and then in living mice. Our data showed the potential to turn on a different copy of a gene that could compensate for the mutation that Terry had. Excited by our data, Rich assembled a team of translational scientists who could turn our findings into an FDA-approved drug.Rich's success in leading the development effort for Terry's drug is an example that drug development can happen relatively fast if a patient is the focus of the effort, just like Tim Yu's efforts in developing a drug for Mila (https://answers.childrenshospital.org/milasen-batten-disease/). Although this story did not unfold the way we had hoped, we are now determined to make sure that Terry's legacy is not forgotten. He was a brave individual who consented to trying an experimental drug because he saw it as a way of fighting back and not accepting the predetermined fate written in his genes.Just as many lives were sacrificed during the early years of space travel, the process of translating gene therapy, despite extensive safety testing in animals, is still not without casualty. The findings from Terry's case as well as other recent deaths in gene therapies provide painful but valuable lessons that will help de-risk the translation of gene therapies for future patients. Terry—thank you for being our astronaut and willing to brave the unknowns of safe travel for future generations. Wherever you are—we hope you are having the adventure of a lifetime, free from the constraints of your physical body.Angela Lek, PhDMuscular Dystrophy AssociationMonkol Lek, PhDYale University School of MedicineMy brother, Terry, was the bravest person I knew. For more than 27 years, he waged a silent war against an impossible enemy. But the disease did not define Terry. His ability to overcome impossible odds inspired me to try and do the same.I am not sure where to start this piece. The memories and tears burn through me as I write these words. Memories of good times—times seared into my memory of Terry laughing or joking with me about something our dad did. Memories of Terry's ingenuity as we built a new car washing business. Terry figuring out how to set up our phones and developing a system to enable us to view and control the car wash from hundreds of miles away, giving us the freedom to go where we needed to go.My mind flashes back to years before. It was a beautiful summer day in our hometown in upstate NY when we were kids playing catch outside with my dad and grandpa. My brother teased my grandmother while catching a ball my dad threw. Or when Terry and I had a hot dog stand outside my parents' convenience store as kids one hot summer, neither of us wanted to be there but we banded together as brothers. Or to the fond memories I have of waking up on Saturday mornings to play Star Wars Galaxies with Terry as kids, a series that defined our brotherhood—good versus evil, fighting against impossible odds for love and selflessness.As his disease progressed, we thought Terry relied on us. But Terry was a doer and, over the years, my family and I came to rely on him for so many things, many things that we never realized until his absence made it painfully clear just how much we relied on him.I could write endless pages about Terry's selfless acts. His grit, his determination, and humility in light of a situation that would make most people want to crawl into a hole and disappear. His stoicism unwavering as the enemy continued to encroach and slowly robbed him of his legs, his arms, and eventually his life.You see, Terry was incredibly smart. He graduated at the top of his high school class, went on to study information science at Cornell University and then took a role at Cornell supporting the information science program. Terry's dedication and loyalty to those around him was unparalleled. When someone needed help, Terry was always the first to answer the call. Whether it was a professor who needed urgent help or my dad needing Terry to fix something at last minute, Terry never said no.One story in particular strikes me—Terry had a professor who gave him a verbal pass on an assignment that included an inaccessible physical component, yet went on to give Terry a bad grade because he did not do that assignment. Frustrated and persistent as hell, Terry attempted to engage the professor dozens of times. The professor ignored his attempts and eventually, rudely, told Terry to stop. Years later, the person who supported the professor left suddenly. Without support and needing help urgently, that same professor turned to Terry, who was no longer a student but rather an employee at Cornell. Despite the wrongs and immorality the professor had inflicted, Terry turned his cheek and helped to enroll dozens of teaching assistants and students into a class at the eleventh hour one Sunday evening. Most people, including myself, would have blown off this old cranky man and left him to his own devices and consequences. Not Terry. Terry was better than that, Terry was better than me. Terry was better than us.As an unaffected brother, I wish Terry's condition was as simple as donating a kidney or a heart. But it was not. When I started Cure Rare Disease I did not know what would come. I just jumped in because there was no one else who was going to help this incredible guy whose heart was as big as the ocean. No one could see how much he loved his family, his cat, Simba, and his dog, Leia. It is easy for researchers, industry, and others to hide behind the abstractness of an unknown patient. But it is not easy to watch your brother deteriorate.We got lucky and found incredible scientists such as Dr. Monkol and Angela Lek who were brave enough to challenge the status quo in hopes that there could be a brighter future. Together, this band of unlikely people—united by a young man whose quiet determination changed more than the most powerful people—were committed to reimagining what was possible in an effort to treat even the rarest disease. Throughout this journey, Terry's hopes waxed and waned with our successes and setbacks. At first, he did not ask much about the progress we were making. But as time went on and we passed checkpoint after checkpoint, I saw hope grow in Terry's eyes. For a time, I thought: we can win, we can do this. Whether it was science, luck, God, or all of those things on our side, we pushed through the impossible to save Terry.But it was Terry's bravery that mattered the most—his bravery to trust us, to knowingly dive into the unknown for a chance to make the world a better place, not for him, but for others like him. This courage set him apart from the rest of us.The world is a darker place without Terry. We laugh less, we smile less, we mourn for a brother and son who was the center of the universe and our reason to live. I mourn for my baby brother, who I miss every single day. I still go to send him a funny TikTok or a new Star Wars game and then remember that he is not here. The body remains but my north star is gone and the pain that remains is love without a place to go.But to give up, to surrender, is to betray Terry. To honor Terry is to carry out his last wishes of making the world better for others like him: to build a system where those forgotten patients, those Terry's, do not have to fear a diagnosis; to fight inequity at every turn; and to hope that someday, I can hug him again.I am sorry we were not good enough, Terry. I am sorry I could not save you. Rest well with our grandparents, Mischief, Simba, Leia, and our family. I will see you again and I love you in this life and the next.The Future of Cure Rare DiseasesI started Cure Rare Disease in an effort to harness the emerging power of gene editing to save Terry. The next 4 years would take us on a journey fit for a movie—from initial in vitro correction of Terry's cells using a newly developed CRISPR transcriptional activator and successful pharmacology studies to a Food and Drug Administration preinvestigational new drug (IND) meeting, an eventual IND submission and the start of a first-in-human clinical trial.The journey brought into the fold hundreds of people from across the world—scientists sacrificing holidays, supporters fueling our mission with their dollars, and a unified passion to use cutting-edge science for the benefit of patients left behind.Along that journey other families, other Terry's, reached out to us in hopes of finding help where none currently exists. Although the clinical trial ended in tragedy, the process and approach used to develop the therapeutic is one which we learned has the potential to help many more.Currently, the mechanism of drug development is one in which large sums of capital are required to advance promising therapeutics into clinical development and eventually commercial approval. The system is designed to favor the treatment of diseases that impact millions or hundreds of thousands of people. With the introduction of the Orphan Drug Act in 1983, industry was incentivized to develop drugs for rare diseases such as amyotrophic lateral sclerosis, Huntington's, and others that impact <200,000 Americans through extended market exclusivity and tax incentives thought to offset the fewer number of patients and potentially smaller commercial markets. The act was effective in catalyzing rare disease drug development, but many “ultra-rare” diseases have far few patients to ever attract commercial interest. And without commercial interest, there is no mechanism to advance a program from bench to bedside.At a macro level, this lack of mechanism impacts the lives of millions of Americans, the families who provide care, and the communities that rally in hopes of attracting commercial interest despite too few patients. But the macro level fails to illustrate the human element behind these patients. It fails to illustrate that each and every patient impacted by a rare disease has a family who loves them, that they have dreams and fears and a desire to cling to life despite how many others may be impacted by their disease.My brother, Terry, fell into this category—although impacted by a rare disease, he harbored an ultra-rare mutation that rendered him ineligible for virtually any clinical trial, the few that existed in the 2000s and 2010s. With the emergence of gene therapy and precision medicine, the technology to develop therapeutics for these patients exists and continues to advance every day. Yet, the current mechanisms of drug development fall short for the rarest of the rare.Thus was born Cure Rare Disease and the journey to develop a therapeutic for a single patient by bringing together the brightest minds to harness the incredible power of cutting-edge science to save a life.Fast forward to 2023. Bruised and battered, we rise again to continue the work we started in 2018. Although we were too late to save Terry, the memory of his legacy empowers us to push on. Our researchers, our families, and the patients who collectively have a different understanding of the risks posed by being on that bleeding edge of science hold on to hope for a brighter future.The mission continues, and has grown, to over 15 drug development programs—ranging from rare mutations of DMD, to a growing number of limb-girdle muscular dystrophy subtypes, to distal myopathies and neurodegenerative diseases. Our research collaborations continue to grow as well. From Massachusetts, Virginia, California to Canada and Europe, we stand united by a burning vision that the world can and must be a better place for those impacted by rare and ultra-rare disease.We are hurt, we are fallible, but our knowledge, insufficient as it may be, continues to grow through the sacrifices of brave heroes like Terry. He is at the heart of everything we do, and we honor his memory by breaking new boundaries, for those who have been forgotten and neglected because their disease is too rare.Our efforts to advance novel gene therapy and gene-editing technologies, develop new better delivery modalities and to forge a path to figuring out how to pay for all of this without placing the financial burden on families who just want to be able to hold their loved ones pushes forward with renewed passion.We are united across geographies, across race and socioeconomics in a shared journey to define a new future, regardless of the number of patients that an individual disease impacts and regardless of industry's desire to help realize that future. This is my call to those with whom this message resonates—the small percentage of game changers this world has to offer—to join us. Together we can, we have, and we will continue to push that bleeding edge forward to capture all who have been forgotten.Richard W. HorganCure Rare DiseaseFiguresReferencesRelatedDetails Volume 0Issue 0 InformationCopyright 2023, by Mary Ann Liebert, Inc., publishersTo cite this article:What We Owe Terry Horgan: Reflections from Providers, Family, and Scientists.Human Gene Therapy.ahead of printhttp://doi.org/10.1089/hum.2023.29247.editorialOnline Ahead of Print:October 12, 2023PDF download