Dimethylglycine Dehydrogenase Deficiency

Pictured: NASA astronaut Jasmin Moghbeli processes Microgravity offers unique advantages when investigating cells and proteins, but collaboration and a strong ethical framework are needed to fully realize its benefits. Pictured: NASA astronaut Jasmin Moghbeli processes liver stem cell samples aboard the International Space Station/ Flickr , NASA Johnson Biomedical research, the bedrock of medical advancements on Earth, has always been a maze of challenges. From the complexities of human biology to the unpredictability of diseases, researchers are in a constant battle with variables that can alter the course of a study. But what if there was a way to sidestep some of these Earth-bound limitations? This is where space, the next frontier in clinical research, comes into play. With its unique environment of microgravity, space offers a fresh perspective for research. In microgravity, where the gravitational pull is much weaker than on Earth, cells and molecules behave differently. This unique environment can provide insights into diseases and their treatments that are impossible to achieve here on Earth. Cell Behavior in the Cosmic Lab One of the most intriguing aspects of space-based research is cells’ behavior in microgravity. On Earth, when cells are grown in labs, they tend to flatten on the surface of culture dishes. However, in space, they take on more natural, three-dimensional shapes, allowing for more in-depth study of diseases and potential treatments. For instance, a study aboard the International Space Station (ISS) is currently exploring how a type of cancer called diffuse midline glioma (DMG) develops. DMG is a brain tumor originating from the central nervous system’s glial cells, often located in the brainstem’s pons region. Predominantly affecting children aged 5-7, DMG constitutes 10–15% of pediatric brain tumors in the U.S., resulting in 150–300 new cases annually. Tragically, the two-year survival rate after diagnosis is below 10% for children with DMG. By studying these DMG cancer cells in space, researchers hope to gain insights into their structure and composition that could lead to more robust and effective treatments. Heart Matters: Cardiac Discoveries in Orbit Cancer takes a heavy toll on humanity, but the burden of cardiovascular disease is even greater, accounting for 20 million fatalities each year globally. Intriguingly, the vast expanse of space may hold the key to potential remedies for heart-related ailments. In 2018, NASA launched a study to explore the development of heart cells, known as cardiomyocytes, in the unique environment of space. This research concluded that in the unique conditions of space, specific sets of stem cells are more likely to develop into heart muscle cells called cardiomyocytes. Building on this insight, another study, MVP Cell-03, concluded that these heart cells not only developed more frequently in space but could also be used to treat heart problems caused by long space flights or heart diseases on Earth. Protein Crystallography in Space While the heart is central to circulating blood, it’s the myriad 20,000 proteins in our bodies that truly govern our physiological functions, driving nearly every chemical process within us. Understanding proteins’ structure can help in developing new medicines. In the unique environment of space, proteins form larger and more orderly crystals than on Earth. This allows scientists a clearer insight into their makeup. For instance, the NanoRacks-PCG Therapeutic Discovery project in space has provided valuable information on proteins associated with leukemia and breast and skin cancers. Similarly, research on the KRAS protein, which is linked to several cancers, has been enhanced by space studies, offering hope for more effective cancer treatments in the future. International Collaborations in Space-Based Clinical Research While individual studies and projects shed light on the potential of space-based research, it takes collaborative efforts on a global scale to truly amplify the impact and reach of these discoveries. In one initiative, Russia’s State Space Corporation, Roscosmos, introduced the “ Kristallizator ” program, which is centered around cultivating distinct protein crystals suitable for X-ray analysis. The knowledge gained from this initiative is paving the way for the development of novel tuberculosis treatments. Meanwhile, the Japan Aerospace Exploration Agency, JAXA, continues its pioneering space work, which has identified potential therapeutic agents for conditions such as Duchenne muscular dystrophy. Challenges in Space-Based Clinical Research The allure of space for clinical research is undeniable, but it comes with unique challenges. First, the logistics of transporting experiments to space are intricate. Launching payloads into space requires meticulous planning, ensuring that the sensitive equipment and samples can withstand the rigors of space travel. The high costs associated with these launches can also be prohibitive. Every kilogram sent to space comes with a hefty price tag, making budgeting a significant concern for researchers. The International Space Station (ISS), one of the primary venues for space-based research, has limited availability. With numerous countries and private entities vying for a spot on the ISS research schedule, securing a slot for research can be competitive. Another concern is the long-term effects of microgravity on the health of the humans tasked with carrying out experiments in space. While we have gleaned some insights from astronauts who have spent extended periods in space, there is still much we don’t know about how prolonged exposure to microgravity might affect our cellular processes, immune system or even DNA. These unknown risks add layers of complexity to research in space. But every challenge presents an opportunity. Innovative Solutions: Paving the Way Forward The beauty of challenges is that they drive innovation. Imagine pop-up labs in space: compact, deployable research stations that can be launched affordably, making space research more accessible to smaller institutions. Telemedicine techniques, already transforming healthcare on Earth, could be adapted for space, allowing real-time consultations between astronauts and Earth-bound experts. And as we look to the future, partnerships between countries and even private companies could lead to shared research spaces in orbit, democratizing access and fostering collaboration. The concept of “space habitats”—self-sustaining environments beyond the ISS—is gaining traction, potentially extending research opportunities. Furthermore, the integration of AI and machine learning in space research can help in real-time data analysis, making research more efficient and actionable. Steering the Ship: Governance in Space-Based Research As we venture deeper into the cosmos, our guiding principles in space research must be firmly rooted in ethics, transparency and collaboration. Disease and drug research, with its inherent complexities, demands a robust and adaptive governance framework, especially when conducted in the unique environment of space. This framework should prioritize collaboration and the ethical use of shared resources in space, ensuring that every space-based laboratory research project adheres to rigorous global standards and responsible practices. The concept of a space research consortium offers a promising solution. By bringing together nations and private stakeholders, this consortium would democratize research opportunities, ensuring that space becomes a shared laboratory for humanity. More than just a collaborative platform, it would set universal ethical standards for research in space. Open-source research, championed by this consortium, would ensure that discoveries made beyond our atmosphere themselves transcend geopolitical boundaries and are accessible and beneficial to all. From Earth to the Stars: A New Chapter in Laboratory Research Space, the final frontier, offers more than just stars and galaxies: It presents a unique canvas for clinical laboratory research. As we decode the mysteries of cells in microgravity and harness the potential of proteins crystallized in space, we’re writing a new chapter in medical science. But this journey, as exhilarating as it is, demands a compass guided by strong collaboration between public and private entities and a deep commitment to ethical usage of shared resources in space. As we set our sights on the cosmos, let’s ensure that our voyage is not just about reaching new heights but also about elevating the standards of research here on Earth for the betterment of all. Deepika Khedekar is a clinical trial lead at IQVIA Inc, a global clinical research organization where she spearheads clinical trial monitoring programs for major pharmaceutical companies. In her 12+ years in the pharmaceutical industry, she led Phase I, II and III clinical trial programs in respiratory and gastrointestinal therapeutics and drugs for leading U.S.- and Australia-based pharmaceutical organizations such as Gilead Sciences, Macleods Pharma, Arrowhead Pharmaceuticals, NoNO Inc., EpimAb and Impact Pharma.

VRW Haelo_EMulate Therapeutics, Dr. Sam Blackman_D September 24 is World Cancer Research Day, and September is Childhood Cancer Awareness Month. BioSpace spoke with leaders from three companies tackling pediatric glioma. Modifi Bio Co-founders Dr. Kingson Lin, Kevin Rakin, Dr. Seth Herzon and Dr. Ranjit Bindra/courtesy Modifi Bio September is Childhood Cancer Awareness Month, which sheds light on the need for new developments in pediatric oncology. For American children, the number one cause of death by disease is cancer. Pediatric gliomas, the most common type of brain tumor in children, are a critical area of focus for oncology research. A Yale School of Medicine team recently published a study outlining their development of a tumor-selective DNA cross-linking agent that targets drug-resistant glioma tumors. Dr. Ranjit Bindra, M.D., Ph.D., a co-lead author of the study and the Harvey and Kate Cushing Professor of Therapeutic Radiology at Yale Medicine, told BioSpace there are a number of complexities when it comes to treating pediatric gliomas. Pediatric Brain Tumors are Unique First of all, research regarding children’s brain tumors tends to mirror what’s worked in the past for adults, but this approach has many flaws. “Pediatric brain tumors have very unique tumor mutations and molecular genetics that are distinct from adult tumors, such that what works in adults typically will not work in kids,” Bindra explained. Secondly, he pointed out the glaring unmet need in rare pediatric cancers overall. Even if cancers such as medulloblastoma or ependymoma are less frequently diagnosed than others, malignant results are devastating to families and entire communities. During his residency at Memorial Sloan Kettering Cancer Center, Bindra witnessed “absolute devastation” from families with children who were diagnosed with rare tumors. “You see a lot of people in absolute shock. They’re thinking about their summer plans for a four-year-old in school, and all of the sudden, they have an incurable brain tumor.” The limited patient population makes it difficult for researchers in the pediatric oncology space to gain funding or grants. Thankfully, companies like CureSearch for Children’s Cancer are helping to drive innovation. The organization contributed to the funding of the DNA repair agent research study. Bindra explained the genetic mutations that happen in pediatric cancers – and all cancers – with a driving analogy. Normal cells are driven into cancers when “a cancer cell takes its foot off the brake and puts its foot down on the gas pedal. Those are what we call two genomic hits.” In precision oncology, these features can be targeted. If the cell is accelerating too fast, a drug can be developed to slow it down. But the intelligent cancer cells are rapidly able to find a way around these drugs, however, which causes resistance over time. The DNA Repair Approach “DNA repair is the process of repairing errors in the genome in cancer,” Bindra noted. Over the past 10 to 15 years, research has shed light on how cancer cells dysregulate the DNA repair process as they grow. “The same function that allowed the cancer cell to form is also an Achilles heel because it’s growing in a situation where it’s inactivated key parts of the DNA repair system,” he continued. The newly developed molecules exploit this Achilles heel, inactivating a DNA repair pathway to selectively kill the cancer cells. “We’re going after what actually created the cancer cell by further destabilizing the genome to the point of no return,” Bindra said. On a higher level, the study shows that “instead of indirectly targeting proteins, you can actually directly modify the DNA.” Based on the novel discovery, Bindra, Seth Herzon, Ph.D. (study co-lead author), Kingson Lin, Ph.D., (study author), and Kevin Rakin (partner HighCape Capital) co-founded Modifi Bio . The new company plans to get the molecule into the clinic by 2024. “Modifi Bio is now rapidly testing these molecules and trying to find the right one that will be able to work in patients,” Bindra said. Tovorafenib Leads to 64% ORR in Phase II Another company working to develop treatments for children’s cancer is Day One Bio . Dr. Samuel Blackman, M.D., Ph.D., co-founder and chief medical officer, told BioSpace the company’s name was inspired by what pediatric oncologists refer to as the Day One Talk. “This is the talk you have with the family when the child is diagnosed with cancer,” said Blackman, who completed his fellowship at Dana-Farber Cancer Institute. “This is where you walk through the diagnosis, the treatment plan, the side effects, the alternatives and what it’s going to be like for the family.” The discussion typically takes several hours and involves many tissues. Blackman said he wants his company to make new drugs to offer at the Day One Talk rather than decades-old chemotherapy options. One of these drugs is tovorafenib (DAY101), an investigational type II pan-RAF kinase inhibitor. The drug is being developed to treat pediatric low-grade glioma (pLGG). Early data from the Phase II FIREFLY-1 trial showed tovorafenib resulted in a 64% overall response rate. The FIREFLY-2 Phase III evaluation of tovorafenib will open later this year, with a full dataset on FIREFLY-1 anticipated in early 2023. Ultra-Low Radio Frequency Energy A unique approach to pediatric glioma treatment comes from EMulate Therapeutics, a clinical-stage therapeutic device company. EMulate’s proprietary platform uses ultra-low radio frequency energy (ulRFE®) to record and replay a molecule’s digital fingerprint. The company’s home-use Hælo system is being investigated as a potential treatment for diffuse midline glioma (DMG). Chris E. Rivera, CEO, told BioSpace , “we have developed a WAV emulates in our technologies,” hence the name EMulate Therapeutics. The system works to “emulate the mechanism of a number of different drugs and chemicals by developing or transitioning the digital electronic signals off of molecules.” EMulate has received the humanitarian device exemption from the FDA to treat DMG. So far, fourteen pediatric patients with DMG and diffuse intrinsic pontine glioma (DIPG) have been treated with the Hælo system in a compassionate use protocol. All but one of the patients was under the age of 18. The device was worn on the back of the head for close proximity to the tumor, and a WAV the chemotherapy drug paclitaxel was played through a coil. Twelve of the 14 patients survived for at least a year. The company hopes to replicate these results in an upcoming Phase III study. “We think this will have a meaningful clinical impact for these patients, the physicians and their families.” With median survival for DMG being less than a year on average, Rivera sees treatment as a “high, high unmet need.” He said many people’s initial reaction to the company’s technology involves disbelief. “When you’re on the leading edge of something different, it can be hard to keep an open mind,” he said. “The challenges in not only brain cancer, but in children’s brain cancer, are daunting. I think we should keep an open mind and look at all potential avenues and aspects to treat these patients.”