(Press-News.org) TORONTO – A team of researchers based at the University of Toronto’s (U of T) Leslie Dan Faculty of Pharmacy has discovered a novel ionizable lipid nanoparticle that enables muscle-focused mRNA delivery while minimizing off-target delivery to other tissues. The team also showed that mRNA delivered by the lipid nanoparticles investigated in their study triggered potent cellular-level immune responses as a proof-of-concept melanoma cancer vaccine.
The study, led by Bowen Li, assistant professor, Leslie Dan Faculty of Pharmacy, U of T, was published this week in Proceedings of the National Academy of Sciences (PNAS).
Called iso-A11B5C1, the new lipid nanoparticle demonstrates exceptional mRNA delivery efficiency in muscle tissues while also minimizing unintended mRNA translation in organs such as the liver and spleen. Additionally, study results show that intramuscular administration of mRNA formulated with this nanoparticle caused potent cellular immune responses, even with limited expression observed in lymph nodes.
“Our study showcases for the first time that mRNA lipid nanoparticles can still effectively stimulate a cellular immune response and produce robust anti-tumor effects, even without direct targeting or transfecting lymph nodes,” said Li. “This finding challenges conventional understandings and suggests that high transfection efficiency in immune cells may not be the only path to developing effective mRNA vaccines for cancer.”
Reducing off-target effects important step to increase safety of potential therapies
Lipid nanoparticles, also called LNPs, are crucial for delivering mRNA-based therapies including COVID-19 mRNA vaccines that were used worldwide during the recent global pandemic. However, many LNP designs can inadvertently result in substantial mRNA expression in off-target tissues and organs like the liver or heart, resulting in often treatable but unwanted side-effects. The drive to improve the safety of mRNA therapies that have the potential to treat a broad range of diseases means there is an urgent need for LNPs designed to minimize these off-target effects, explains Li who is also a recent recipient of the Gairdner Early Career Investigator Award.
The new research shows that, compared to the current benchmark LNP developed by the Massachusetts-based biotechnology company Moderna, iso-A11B5C1 demonstrated a high level of muscle-specific mRNA delivery efficiency. It also triggered a different kind of immune response than what is seen in vaccines used to treat infectious diseases. “Interestingly, iso-A11B5C1 triggered a lower humoral immune response, typically central to current antibody-focused vaccines, but still elicited a comparable cellular immune response. This finding led our team to further explore this as a potential cancer vaccine candidate in a melanoma model, where cellular immunity plays a pivotal role,” said Li.
The interdisciplinary research team that conducted the study includes Jingan Chen, a PhD trainee from the Institute of Biomedical Engineering at U of T, and Yue Xu, a postdoctoral researcher in the Li lab and a research fellow with PRiME, U of T’s cross-institutional precision medicine initiative. “Although iso-A11B5C1 showed limited capacity to trigger humoral immunity, it effectively initiated cellular immune responses through intramuscular injection,” said Chen. “The substantial anti-tumor effects observed with iso-A11B5C1 underscore its promise as a viable candidate for cancer vaccine development.”
New platform allows for faster, more precise lipid design
The research team identified iso-A11B5C1 by using an advanced platform developed to quickly create a range of chemically diverse lipids for further testing. This platform, newly introduced as part of the study, overcomes several challenges seen in previous research by streamlining the process of creating ionizable lipids that have a high potential to be translated into therapies. By rapidly combining three different functional groups, hundreds to thousands of chemically diverse ionizable lipids can be synthesized within 12 hours. “Here we report a powerful strategy to synthesize ionizable liquids in a one-step chemical reaction,” said Xu. “This platform provides new insights that could help guide lipid design and evaluation processes going forward and allows the field to tackle challenges in RNA delivery with a new level of speed, precision and insight.”
- 30 –
Leslie Dan Faculty of Pharmacy, University of Toronto
(416) 978 - 7117
About the Leslie Dan Faculty of Pharmacy, University of Toronto
The Leslie Dan Faculty of Pharmacy at the University of Toronto is Canada's top-ranked faculty of pharmacy, offering cutting-edge undergraduate and graduate programs. We are globally recognized for impactful pharmaceutical sciences research and fostering expert and innovative clinical practice. Our scientific research focuses on the role of pharmacists in the health care system, and the full scope of drug discovery and delivery. We advance education programs that develop leaders in science and clinical practice and work to strengthen the link between research, education, and patient care.
University of Toronto researchers discover new lipid nanoparticle that shows muscle-specific mRNA delivery, reduces off-target effects.
Study findings make significant contribution to generating tissue-specific ionizable lipids and prompts rethinking of mRNA vaccine design principles
ELSE PRESS RELEASES FROM THIS DATE:
Evolving insights in blood-based liquid biopsies for prostate cancer interrogation
“In the United States, 288,300 new cases of prostate cancer are estimated for 2023 [...]” BUFFALO, NY- December 8, 2023 – A new research perspective was published in Oncoscience (Volume 10) on November 30, 2023, entitled, “Evolving insights in blood-based liquid biopsies for prostate cancer interrogation.” During the last decade, blood sampling of cancer patients aimed at analyzing the presence of cells, membrane-bound vesicles, or molecules released by primary tumors or metastatic growths emerged as an alternative to traditional tissue biopsies. The advent of this minimally invasive approach, known as blood-based liquid biopsy, ...
Finding the most heat-resistant substances ever made
The most durable, heat-resistant materials ever made could be hiding in plain sight. The U.S. Department of Defense wants to know if minerals and rocks found on Earth and in space hold the secrets of next-generation high-temperature materials. To find out, the DOD awarded $6.25 million through its Multidisciplinary University Research Initiative, or MURI, to a team from the University of Virginia and Arizona State University. The group is led by UVA’s Elizabeth J. Opila, the Rolls-Royce Commonwealth Professor and chair of the Department of Materials Science and Engineering. The ...
Time-tested magnesium oxide: Unveiling CO2 absorption dynamics
Magnesium oxide is a promising material for capturing carbon dioxide directly from the atmosphere and injecting it deep underground to limit the effects of climate change. But making the method economical will require discovering the speed at which carbon dioxide is absorbed and how environmental conditions affect the chemical reactions involved. Scientists at the Department of Energy’s Oak Ridge National Laboratory analyzed a set of magnesium oxide crystal samples exposed to the atmosphere for decades, and another for days to months, to gauge the reaction rates. They found that carbon ...
Engaging heterosexual men more effectively could slash HIV infections in Uganda
A study looking at 15 years of HIV transmission and suppression in Uganda reveals how closing gender gaps in treatment could slash infection rates. Providing more heterosexual men with easy access to HIV treatment and care could help to suppress the virus and rapidly cut transmission to their female partners, shows a new study published in Nature Microbiology. The research, led by scientists from Imperial College London and the Rakai Health Sciences Program in Uganda, analysed 15 years of data from 2003-2018, during which the US President’s Emergency Plan For AIDS ...
A fork in the rhod: Janelia researchers unveil comprehensive collection of rhodamine-based fluorescent dyes
When Senior Scientist Jonathan Grimm came to Janelia 13 years ago, he didn’t know much about fluorescence or fluorescent dyes. But as an organic chemist who had been working in drug discovery at Merck, he certainly knew a thing or two about medicinal chemistry. On a whim, Grimm and Janelia Senior Group Leader Luke Lavis decided to try using a mainstay medicinal chemistry reaction Grimm had picked up in the pharmaceutical industry to improve centuries-old dye chemistry. They thought this approach could allow access to completely new, previously inaccessible rhodamines – molecules Lavis had been working to make brighter and longer-lasting so they could be ...
The Gerontological Society of America congratulates new 2023 awardees
The Gerontological Society of America (GSA) — the country’s largest interdisciplinary organization devoted to the field of aging — is proud to acknowledge the work of 34 outstanding individuals through its prestigious awards program. GSA salutes outstanding research, recognizes distinguished leadership in teaching and service, and fosters new ideas through a host of awards. Nominated by their peers, the recipients’ achievements serve as milestones in the history and development of ...
Texas A&M Institute part of national effort to harness nuclear laser fusion for limitless energy
Nuclear fusion, the process that powers the sun, is the ultimate source of energy for all life on Earth. On the sun, deuterium and tritium nuclei combine to produce an alpha particle (the nucleus of a helium atom) and a neutron. The dream is to do the same down here, on Earth, in a controlled manner. It’s for good reason that harnessing fusion energy is one of the greatest scientific and technological challenges of the 21st century. Fusion requires the fuel to be heated to more than 100 million degrees (10 times hotter than the core of the sun). Practical fusion energy also requires that the burning fuel is kept at these hot temperatures long enough so that energy ...
How health system hesitancies contributed to COVID risks
More than 1.2 million people have died in the United States during the COVID-19 pandemic to date, more documented deaths than any other nation on Earth. While many have attributed the high death toll on widespread personal hesitancy to wear masks, avoid crowded places or receive vaccines once they were developed, there were several “system hesitancies” that contributed to the tragic outcomes that need addressing, according to an analysis published Dec. 6, 2023, in Health Affairs Forefront. The analysis ...
Stand Up to Cancer names Julian Adams, Ph.D., President and CEO
LOS ANGELES – December 8, 2023 – Stand Up To Cancer® (SU2C) today announced the appointment of Julian Adams, Ph.D., as president and chief executive officer, which will be effective on January 1, 2024. Adams had previously served on SU2C’s Scientific Advisory Committee since 2008, and officially joined SU2C in July 2023 in the newly created position of chief science officer. He succeeds Russell Chew, who joins SU2C’s Board of Directors. Adams is a longtime oncology researcher and pharmaceutical industry senior executive specializing in drug discovery and development in cancer. With this appointment, Adams assumes management responsibility for SU2C’s overall ...
Immersive VR goggles for mice unlock new potential for brain science
Northwestern University researchers have developed new virtual reality (VR) goggles for mice. Besides just being cute, these miniature goggles provide more immersive experiences for mice living in laboratory settings. By more faithfully simulating natural environments, the researchers can more accurately and precisely study the neural circuitry that underlies behavior. Compared to current state-of-the-art systems, which simply surround mice with computer or projection screens, the new goggles provide a leap in advancement. In current systems, mice can still see the lab environment peeking out from behind the screens, and the screens’ ...
LAST 30 PRESS RELEASES:
Small and overlooked: Amount of repetitive DNA in blood hints at cancer early
Study determines the original orientations of rocks drilled on Mars
Illinois study: Supporting disease-challenged broiler chickens through nutrition
Communities severed by roads and traffic experience a larger number of collisions in New York City
Study shows new class of antivirals that works against SARS-CoV-2
Cost of direct air carbon capture to remain higher than hoped
Unraveling the mystery of chiton visual systems
Case Western Reserve University-led research team discovers new method to test for oral cancer
Firearm access and gun violence exposure are common in Black and native communities
New AI smartphone tool accurately diagnoses ear infections
Screen time and parent-child talk when children are ages 12 to 36 months
Firearm access and gun violence exposure among American Indian or Alaska native and Black adults
Associations of medical debt with health status, premature death, and mortality in the US
Low-cost liquid tames tooth decay
More than 1/3 illicit drugs sold on the dark web contain unexpected substances
A better way to deliver fetal therapy for serious genetic disorders
Researchers develop amphibian-inspired camouflage skin
Network of quantum sensors boosts precision
Robotic hip exoskeleton shows promise for helping stroke patients regain their stride
Conservation value of field research stations grossly misunderstood and underfunded according to 173 conservation scientists in new study
Study underscores social factors of low breast cancer screening in the US
Nanomedicine research aims to transform treatment of aortic aneurysms
HIV medication can be used safely with gender-affirming hormone therapy
Gene-edited lymphocytes and the path toward ‘off-the-shelf’ therapy against cervical cancer
Humans have driven the Earth’s freshwater cycle out of its stable state
Exposure to different kinds of music influences how the brain interprets rhythm
Study shows differences in how patients with impulse control disorder process consequences
Improving access to early-stage lung cancer care in Europe
Low iron levels resulting from infection could be key trigger of long COVID
Swapping meat for Quorn lowers bad cholesterol by 10-percent[Press-News.org] University of Toronto researchers discover new lipid nanoparticle that shows muscle-specific mRNA delivery, reduces off-target effects.
Study findings make significant contribution to generating tissue-specific ionizable lipids and prompts rethinking of mRNA vaccine design principles