Noor Momin, Stephenson Foundation Term Assistant Professor of Innovation
While growing up, Noor Momin, who joined the Department of Bioengineering in January as the Stephenson Foundation Term Assistant Professor of Innovation, imagined becoming a physician. Becoming a doctor seemed like a tangible way for someone interested in science to make a difference. Not until college did she realize the impact she could have as a bioengineer instead.
“I was taping microscope slides together,” Momin recalls of her initial experience as an undergraduate researcher at the University of Texas at Austin. “I didn’t even know what a Ph.D. was.”
It wasn’t until co-authoring her first paper, which explores how lipids, the water-repelling molecules that make up cell membranes (and also fats and oils), can switch between more fluid and less fluid arrangements, that Momin understood the degree to which bioengineering can influence medicine. “Someone could potentially use that paper for drug design,” Momin says.
As Momin sees it, the conventional wisdom of treating the heart like a mechanical pump, whose pipes can be replaced or whose throughput can be treated to prevent clogging in the first place, overshadows the immune system’s critical role in the development of heart disease.
Kaitlin Mrksich, an undergraduate student in Penn Bioengineering, was honored with the Student Award for Outstanding Research (Undergraduate) by the Society for Biomaterials (SFB). This prestigious award recognizes undergraduate students who have shown outstanding achievement in biomaterials research.
Mrksich is a third-year student from Hinsdale, Illinois. She is interested in developing drug delivery systems that can serve as novel therapeutics for a variety of diseases. She works in the lab of Michael Mitchell, Associate Professor in Bioengineering. In the Mitchell Lab, Mrksich investigates the ionizable lipid component of lipid nanoparticles for mRNA delivery.
“In Kaitlin’s independent projects, she has focused on probing the role of lipophilicity and chirality for LNP-mediated mRNA delivery,” Mitchell said in the award announcement. “She has synthesized dozens of unique lipids, formulated these lipids into LNPs, and evaluated their potential for mRNA delivery in vivo and in primary T cells. She has been able to deduce structure-function relationships that help explain the role of lipid hydrophobicity in the delivery of mRNA by LNPs. Her findings have not only been instrumental in helping our lab design better LNPs but will also provide fundamental knowledge that will benefit all labs working on LNP technology.”
In addition to her academic activities, Mrksich is also the President of the Penn Biomedical Engineering Society (BMES), where she plans community-building and professional-development events for bioengineering majors, and the visit coordinator for special programs for the Kite and Key Society, where she organizes virtual programming to introduce prospective students to Penn. She also tutors a West Philadelphia high school student in chemistry as part of the West Philadelphia Tutoring Project and is a member of Tau Beta Pi engineering honor society and Sigma Kappa sorority. After graduating, she plans to pursue an M.D.-Ph.D. in Bioengineering.
Read the full list of 2024 SFB award recipients here.
Ajay Thatte, Benjamin Nachod, Rohan Palanki, Kelsey Swingle, Alex Hamilton, and Michael Mitchell (Left to Right – Courtesy of the Mitchell Lab)
Autoimmune disorders are among the most prevalent chronic diseases across the globe, affecting approximately 5-7% of the world’s population. Emerging treatments for autoimmune disorders focus on “adoptive cell therapies,” or those using cells from a patient’s own body to achieve immunosuppression. These therapeutic cells are recognized by the patient’s body as ‘self,’ therefore limiting side effects, and are specifically engineered to localize the intended therapeutic effect.
In treating autoimmune diseases, current adoptive cell therapies have largely centered around the regulatory T cell (Treg), which is defined by the expression of the Forkhead box protein 3, orFoxp3. Although Tregs offer great potential, using them for therapeutic purposes remains a major challenge. In particular, current delivery methods result in inefficient engineering of T cells.
Tregs only compose approximately 5-10% of circulating peripheral blood mononuclear cells. Furthermore, Tregs lack more specific surface markers that differentiate them from other T cell populations. These hurdles make it difficult to harvest, purify and grow Tregs to therapeutically relevant numbers. Although there are additional tissue-resident Tregs in non-lymphoid organs such as in skeletal muscle and visceral adipose tissue, these Tregs are severely inaccessible and low in number.
“The major challenges associated with ex vivo (outside the body) cell engineering are efficiency, toxicity, and scale-up: our mRNA lipid nanoparticles (mRNA LNPs) allow us to overcome all of these issues,” says Mitchell. “Our work’s novelty comes from three major components: first, the use of mRNA, which allows for the generation of transient immunosuppressive cells; second, the use of LNPs, which allow for effective delivery of mRNA and efficient cell engineering; and last, the ex vivo engineering of primary human T cells for autoimmune diseases, offering the most direct pipeline for clinical translation of this therapy from bench to bedside.”
“To our knowledge, this is one of the first mRNA LNP platforms that has been used to engineer T cells for autoimmune therapies,” he continues. “Broadly, this platform can be used to engineer adoptive cell therapies for specific autoimmune diseases and can potentially be used to create therapeutic avenues for allergies, organ transplantation and beyond.”
Delivering the Foxp3 protein to T cells has been difficult because proteins do not readily cross the cell membrane. “The mRNA encodes for Foxp3 protein, which is a transcription factor that makes the T cells immunosuppressive rather than active,” explains first author Ajay Thatte, a doctoral student in Bioengineering and NSF Fellow in the Mitchell Lab. “These engineered T cells can suppress effector T cell function, which is important as T cell hyperactivity is a common phenotype in autoimmune diseases.”
(Left to right): Mike Mitchell, Noor Momin, and David Meaney recording the Innovation & Impact podcast.
In the most recent episode of the Penn Engineering podcast Innovation & Impact, titled “RNA: Past, Present and Future,” David F. Meaney, Senior Associate Dean of Penn Engineering and Solomon R. Pollack Professor in Bioengineering, is joined by Mike Mitchell, Associate Professor in Bioengineering, and Noor Momin, who will be joining Penn Engineering as an Assistant Professor in Bioengineering early next year, to discuss the impact that RNA has had on health care and biomedical engineering technologies.
Mitchell outlines his lab’s research that spans drug delivery, new technology in protecting RNA and its applications in treating cancer. Momin details her research, which is focused on optimizing the immune system to protect against illnesses such as cardiovascular diseases and cancer. With Meaney driving the discussion around larger questions, including the possibility of a cancer vaccine, the three discuss what they are excited about now and where the field is going in the future with these emerging, targeted treatments.
On September 14, Wexford Science & Technology, LLC and the University of Pennsylvania announced that the University has signed a lease for new laboratory space that will usher in a wave of novel vaccine, therapeutics, and engineered diagnostics research to West Philadelphia. Research teams from Penn are poised to move into 115,000 square feet of space at One uCity Square, the 13-story, 400,000 square foot purpose-built lab and office building within the vibrant uCity Square Knowledge Community being developed by Wexford. This is the largest lease in the building, encompassing four floors, and bringing the building to over 90% leased. The building currently includes industry tenants Century Therapeutics (NASDAQ: IPSC), Integral Molecular, Exponent (NASDAQ: EXPO), and Charles River Laboratories (NYSE: CRL).
The new University space will house Penn Medicine’s Institute for RNA Innovation and Penn Engineering’s Center for Precision Engineering for Health, underscoring the University’s commitment to a multi-disciplinary and collaborative approach to research that will attract and retain the best talent and engage partners from across the region. Penn’s decision to locate at One uCity Square reinforces uCity Square’s evolution as a central cluster of academic, clinical, commercial, entrepreneurial, and amenity spaces for the area’s innovation ecosystem, and further cements Philadelphia’s position as a top life sciences market.
Jonathan Epstein, MD, Executive Vice Dean and Chief Scientific Officer of Penn Medicine, shared his anticipation for the opportunities that lie ahead: “Penn Medicine is proud to build on its existing clinical presence in uCity Square and establish an innovative and collaborative research presence at the heart of uCity Square’s multidisciplinary innovation ecosystem. This strategic move underscores our commitment to accelerating advancements in biomedical research, industry collaboration, and equipping our talented teams with the resources they need to shape the future of healthcare.”
Locating the Penn Institute for RNA Innovation in the heart of the uCity Square community brings together researchers across disciplines who are already pursuing new vaccines and treatments, and better ways to deliver them. Their shared work will help to power the next phase of vaccine discovery and development.
Likewise, anchoring the work of Penn Engineering’s Center in the One uCity Square space will allow the School’s multi-disciplinary researchers and their collaborators to advance new clinical and diagnostic methods that will focus on intelligent therapeutics, genome design, diagnostics for discovery of human biology, and engineering the human immune shield.
“Penn Engineering has made a substantial commitment to precision engineering for health, an area that is not only important and relevant to engineering, but also critical to the future of humanity,” said Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. “The space in One uCity Square will add another 30,000 square feet of space for our engineers to develop technologies that will fight future pandemics, cure incurable diseases, and extend healthy life spans around the world.”
Spearheading the Penn Institute for RNA Innovation will be Drew Weissman, MD, PhD, the Roberts Family Professor for Vaccine Research, who along with Katalin Karikó, PhD, adjunct professor of Neurosurgery, discovered foundational mRNA technology that enabled the creation of vital vaccine technology, including the FDA-approved mRNA-based COVID-19 vaccines developed by Pfizer-BioNTech and Moderna.
In this new space at One uCity Square, Weissman and his research team and collaborators will further pursue their groundbreaking research efforts with a goal to develop new therapeutics and vaccines and initiate clinical trials for other devastating diseases.
In addition, two established researchers will join the Institute at One uCity Square: Harvey Friedman, MD, a professor of Infectious Diseases, who leads a team researching various vaccines. He will be joined by Vladimir Muzykantov, MD, PhD, Founders Professor in Nanoparticle Research, who focuses on several projects related to targeting the delivery of drugs, including mRNA, to create more effective, targeted pathways to deliver drugs to the vascular system, treating a wide range of diseases that impact the brain, lung, heart, and blood.
Dan Hammer, Alfred G. and Meta A. Ennis Professor in the Departments of Bioengineering and Chemical and Biomolecular Engineering in Penn Engineering and Director of the Center for Precision Engineering for Health, will oversee the Center’s innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. The Center will bring together scholars from all departments within Penn Engineering and will help to foster increased collaboration with campus colleagues at Penn’s Perelman School of Medicine and with industry partners.
Joining the Center researchers in One uCity Square are Noor Momin, Sherry Gao, and Michael Mitchell. Noor Momin, who will join Penn Engineering in early 2024 as an assistant professor in Bioengineering, will leverage her lab’s expertise in cardiovascular immunology, protein engineering and pharmacokinetic modeling to develop next-generation treatments and diagnostics for cardiovascular diseases.
The award recognizes faculty who are conducting some of the most innovative and impactful studies in the field of biomedical engineering. Recipients will present their research and be officially recognized at the BMES Annual Meeting in October.
Mitchell is being honored for creating an RNA nanoparticle therapy that stops the spread of the deadly bone marrow cancer multiple myeloma and helps to eliminate it altogether. Known for being difficult to treat, the disease kills over 100,000 people every year.
“We urgently need innovative, effective therapies against this cancer,” Mitchell says. “The nanotechnology we developed can potentially serve as a platform to treat multiple myeloma and other bone marrow-based malignancies.”
Mitchell, along with Christian Figuerora-Espada, a doctoral student in Bioengineering, previously published a study in PNAS describing how their RNA nanoparticle therapy stops multiple myeloma from moving through the blood vessels and mutating. In their current paper in Cellular and Molecular Bioengineering, which expands upon this RNA nanoparticle platform, they show that inhibition of both multiple myeloma migration and adhesion to bone marrow blood vessels, combined with an FDA-approved multiple myeloma therapeutic, extends survival in a mouse model of multiple myeloma.
Chimeric antigen receptor T cell (CAR T) therapy has delivered promising results, transforming the fight against various forms of cancer, but for many, the therapy comes with severe and potentially lethal side effects. Now, a research team led by Michael Mitchell of the School of Engineering and Applied Science has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. (Image: iStock / Meletios Verras)
In recent years, cancer researchers have hailed the arrival of chimeric antigen receptor T cell (CAR T) therapy, which has delivered promising results, transforming the fight against various forms of cancer. The process involves modifying patients’ T-cells to target cancer cells, resulting in remarkable success rates for previously intractable forms of cancer.
Six CAR T cell therapies have secured FDA approval, and several more are in the pipeline. However, these therapies come with severe and potentially lethal side effects, namely cytokine release syndrome (CRS) and neurotoxicity. These drawbacks manifest as a range of symptoms—from high fever and vomiting to multiple organ failure and patient death—posing significant challenges to broader clinical application.
“Addressing CRS and neurotoxicity without compromising the therapeutic effectiveness of CAR T cells has been a complex challenge,” says Mitchell.
He says that unwanted interactions between CAR T and immune cells called macrophages drive the overactivation of macrophages, which in turn result in the release of toxic cytokines that lead to CRS and neurotoxicity.
“Controlling CAR T-macrophage interactions in vivo is difficult,” Mitchell says. “So, our study introduces a materials engineering-based strategy that involves incorporating a sugar molecule onto the surface of CAR T cells. These sugars are then used as a reactive handle to create a biomaterial coating around these cells directly in the body, which acts as a ‘suit of armor,’ preventing dangerous interactions with macrophages.”
First author Ningqiang Gong, a postdoctoral researcher in the Mitchell Lab, elaborates on the technique, “We attached this sugar molecule to the CAR T cells using metabolic labeling. This modification enables the CAR T cells to attack cancer cells without any hindrance.”
“When symptoms of CRS begin to manifest, we introduce another molecule—polyethylene glycol (PEG)—to create the suit of armor, which effectively blocks dangerous interactions between these engineered T cells, macrophages, and the tumor cells themselves,” Gong says.
(From left to right) Xuexiang Han, Michael Mitchell and Mohamad-Gabriel Alameh
The COVID-19 vaccine swiftly undercut the worst of the pandemic for hundreds of millions around the world. Available sooner than almost anyone expected, these vaccines were a triumph of resourcefulness and skill.
Messenger RNA vaccines, like the ones manufactured by Moderna or Pfizer/BioNTech, owed their speed and success to decades of research reinforcing the safety and effectiveness of their unique immune-instructive technology.
In addition to outlining a more flexible and effective COVID-19 vaccine, this work has potential to increase the scope of mRNA vaccines writ large, contributing to prevention and treatment for a range of different illnesses.
Michael Mitchell, associate professor in Penn Engineering’s Department of Bioengineering, Xuexiang Han, postdoctoral fellow in Mitchell’s lab, and Mohamad-Gabriel Alameh, postdoctoral fellow in Drew Weissman’s lab at Penn Medicine and incoming assistant professor in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, recently published their findings in Nature Nanotechnology.
mRNA, or messenger ribonucleic acid, is the body’s natural go-between. mRNA contains the instructions our cells need to produce proteins that play important roles in our bodies’ health, including mounting immune responses.
The COVID-19 vaccines follow suit, sending a single strand of RNA to teach our cells how to recognize and fight the virus.
Led by Michael Mitchell and David Issadore of the School of Engineering and Applied Science, a team of researchers has developed a platform that could rapidly accelerate the development of mRNA-based lipid nanoparticle vaccines and therapeutics at both the small and large scale, SCALAR. (Image: iStock / Anatoly Morozov)
Following the global COVID-19 pandemic, the development and rapid deployment of mRNA vaccines highlighted the critical role of lipid nanoparticles (LNPs) in the context of pharmaceuticals. Used as the essential delivery vehicles for fragile RNA-based therapies and vaccines, LNPs protect the RNA from degradation and ensure effective delivery within the body.
Despite their critical importance, the large-scale manufacturing of these LNPs saw numerous bottlenecks during the pandemic, underscoring the need for scalable production techniques that could keep pace with global demand.
Now, in a paper published in the Proceedings of the National Academy of the Sciences, researchers at the University of Pennsylvania describe how the Silicon Scalable Lipid Nanoparticle Generation platform (SCALAR), a reusable silicon- and glass-based platform designed to transform the production landscape of LNPs for RNA therapeutics and vaccines, offers a scalable and efficient solution to the challenges exposed during the COVID-19 crisis.
“We’re excited to create a piece of technology platform that bridges the gap between small-scale discovery and large-scale manufacturing in the realm of RNA lipid nanoparticle vaccines and therapeutics,” says co-author Michael Mitchell, associate professor of bioengineering in the School of Engineering and Applied Science at Penn. “By doing so, we’ve effectively leapfrogged the clunky, time-consuming, and costly barriers that slow down the production ramp-up of promising new RNA medicines and vaccines.”
The intricacies of RNA-based therapies require the RNA to be encased in a delivery system capable of navigating the body’s biological obstacles. LNPs fulfill this role, allowing the RNA to reach the intended cells for maximum therapeutic impact. SCALAR aims to take this a step further, allowing for an unprecedented three orders of magnitude scalability in LNP production rates, addressing the speed and consistency bottlenecks that hinder existing methods.
Sarah Shepherd, the first author of the paper and a recent Ph.D. graduate who worked in the Mitchell Lab, says, “With SCALAR, we’re not just reacting to today’s challenges but proactively preparing for tomorrow’s opportunities and crises. This technology is flexible, uses mixing architectures well-documented in microfluidics, and is scalable enough to meet future demands in real time. That’s an enormous leap forward for the field.”
Shepherd says that SCALAR builds on prior work from the Mitchell lab and is based on a microfluidic chip platform. Akin to a computer chip, wherein a computer’s electrically integrated circuit has numerous little transistors transporting signals as ones or zeroes to produce an output, the SCALAR microchip precisely controls their two key reagents, lipids and RNA, to generate LNPs.
Genetic diseases that involve the central nervous system (CNS) often impact children before birth, meaning that once a child is born, irreversible damage has already been done. Given that many of these conditions result from a mutation in a single gene, there has been growing interest in using gene editing tools to correct these mutations before birth.
However, identifying the appropriate vehicle to deliver these gene editing tools to the CNS and brain has been a challenge. Viral vectors used to deliver gene therapies have some potential drawbacks, including pre-existing viral immunity and vector-related adverse events, and other options like lipid nanoparticles (LNPs) have not been investigated extensively in the perinatal brain.
Now, researchers in the Center for Fetal Research at Children’s Hospital of Philadelphia (CHOP) and Penn Engineering have identified an ionizable LNP that can deliver mRNA base editing tools to the brain and have shown it can mitigate CNS disease in perinatal mouse models. The findings, published in ACS Nano, open the door to mRNA therapies that could be delivered pre- or postnatally to treat genetic CNS diseases.
The research team began by screening a library of ionizable LNPs – microscopic fat bubbles that have a positive charge at low pH but neutral charge at physiological conditions in the body. After identifying which LNPs were best able to penetrate the blood-brain barrier in fetal and newborn mice, they optimized their top-performing LNP to be able to deliver base editing tools. The LNPs were then used to deliver mRNA for an adenine base editor, which would correct a disease-causing mutation in the lysosomal storage disease, MPSI, by changing the errant adenine to guanine.
The researchers showed that their LNP was able to improve the symptoms of the lysosomal storage disease in the neonatal mouse brain, as well as deliver mRNA base editing tools to the brain of other animal models. They also showed the LNP was stable in human cerebrospinal fluid and could deliver mRNA base editing tools to patient-derived brain tissue.
“This proof-of-concept study – co-led by Rohan Palanki, an MD/PhD student in my lab, and Michael Mitchell’s lab at Penn Bioengineering – supports the safety and efficacy of LNPs for the delivery of mRNA-based therapies to the central nervous system,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery at CHOP and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery. “Taken together, these experiments provide the foundation for additional translational studies and demonstrate base editing facilitated by a nonviral delivery carrier in the NHP fetal brain and primary human brain tissue.”
This story was written by Dana Bate. It originally appeared on CHOP’s website.
