‘RNA worked for COVID-19 vaccines. Could it be used to treat cancer and rare childhood diseases?’

William H. Peranteau, Michael J. Mitchell, Margaret Billingsley, Meghana Kashyap, and Rachel Riley (Clockwise from top left)

As COVID-19 vaccines roll out, the concept of using mRNA to fend off viruses has become a part of the public dialogue. However, scientists have been researching how mRNA can be used to in life-saving medical treatments well before the pandemic.

The “m” in “mRNA” is for “messenger.” A single-stranded counterpart to DNA, it translates the genetic code into the production of proteins, the building blocks of life. The Moderna and Pfizer COVID-19 vaccines work by introducing mRNA sequences that act as a set of instructions for the body to produce proteins that mimic parts of the virus itself. This prepares the body’s immune response to recognize the real virus and fight it off.

Because it can spur the production of proteins that the body can’t make on its own, mRNA therapies also have the potential to slow or prevent genetic diseases that develop before birth, such as cystic fibrosis and sickle-cell anemia.

However, because mRNA is a relatively unstable molecule that degrades quickly, it needs to be packaged in a way that maintains its integrity as its delivered to the cells of a developing fetus.

To solve this challenge, Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is researching the use of lipid nanoparticles as packages that transport mRNA into the cell. He and William H. Peranteau, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at Children’s Hospital of Philadelphia, recently co-authored a “proof-of-concept” paper investigating this technique.

In this study, published in Science Advances, Mitchel examined which nanoparticles were optimal in the transport of mRNA to fetal mice. Although no disease or organ was targeted in this study, the ability to administer mRNA to a mouse while still in the womb was demonstrated, and the results are promising for the next stages of targeted disease prevention in humans.

Mitchel spoke with Tom Avril at The Philadelphia Inquirer about the mouse study and its implications for treatment of rare infant diseases through the use of mRNA, ‘the messenger of life.’

Penn bioengineering professor Michael J. Mitchell, the other senior author of the mouse study, tested various combinations of lipids to see which would work best.

The appeal of the fatty substances is that they are biocompatible. In the vaccines, for example, two of the four lipids used to make the delivery spheres are identical to lipids found in the membranes of human cells — including plain old cholesterol.

When injected, the spheres, called nanoparticles, are engulfed by the person’s cells and then deposit their cargo, the RNA molecules, inside. The cells respond by making the proteins, just as they make proteins by following the instructions in the person’s own RNA. (Important reminder: The RNA in the vaccines cannot become part of your DNA.)

Among the different lipid combinations that Mitchell and his lab members tested, some were better at delivering their cargo to specific organs, such as the liver and lungs, meaning they could be a good vehicle for treating disease in those tissues.

Continue reading Tom Avril’s ‘RNA worked for COVID-19 vaccines. Could it be used to treat cancer and rare childhood diseases?’ at The Philadelphia Inquirer.

Penn Engineering and CHOP Researchers Identify Nanoparticles that Could Be Used in Therapeutic mRNA Delivery before Birth

by Evan Lerner

William H. Peranteau, Michael J. Mitchell, Margaret Billingsley, Meghana Kashyap, and Rachel Riley (Clockwise from top left)

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy. The proof-of-concept study, published today in Science Advances, engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”

Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, is the other co-senior author of the study. The co-first authors are Mitchell Lab members Rachel Riley, a postdoctoral fellow, and Margaret Billingsley, a graduate student, and Peranteau Lab member Meghana Kashyap, a research fellow.

Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.

Read the full story in Penn Engineering Today.

NB: Rachel Riley is now Assistant Professor in Biomedical Engineering at Rowan University.

Christian Figueroa-Espada Named 2020-2021 Hispanic Scholarship Fund Scholar

Christian Figueroa-Espada

Christian Figueroa-Espada, a Penn Bioengineering Ph.D. student and National Science Foundation (NSF) Fellow, was selected as a Hispanic Scholarship Fund (HSF) Scholar from a highly-competitive pool of 85,000 applicants for their 2020-2021 program. One of only 5,100 awardees, Figueroa-Espada’s scholarship comes from the Toyota Motor North America Program. As an HSF Scholar, he has access to a full range of Scholar Support Services, such as career coaching, internship, and full-time employment opportunities, mentoring, leadership development, and wellness resources, including tools for self-advocacy, well-being, and knowledge building.

Born and raised in the Island of Enchantment, Puerto Rico, Figueroa-Espada received his B.S. in Mechanical Engineering from the University of Puerto Rico at Mayagüez, and is currently a second-year Ph.D. student in the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering, where he is funded by the National Science Foundation Graduate Research Fellowship Program (NSF GRFP), the Graduate Education for Minorities (GEM) Fellowship Program, and the William Fontaine Fellowship. His research interests lie in the interface of biomaterials, drug delivery, and immunology – designing RNAi therapeutics for the reprogramming of the tumor microenvironment. His current project focuses on polymer-lipid drug delivery systems to study potential strategies to prevent homing and proliferation of multiple myeloma cancer within the bone marrow microenvironment. This project is part of the Mitchell lab’s recent National Institutes of Health (NIH) New Innovator Award.

“Chris has really hit the ground running on his Ph.D. studies at Penn Bioengineering, developing a new bone marrow-targeted nanoparticle platform to disrupt the spread of multiple myeloma throughout the body,” says Mitchell. “I’m very hopeful that this prestigious fellowship from HSF will permit him to make important contributions to nanomedicine and cancer research.”

Figueroa-Espada’s passion for giving back to his community has allowed him to be involved in many mentorship programs as part of his roles in the Society of Hispanics and Professional Engineers (SHPE), the National Society of Professional Engineers (NSPE), the Society of Women Engineers (SWE), and the Graduate Association of Bioengineers (GABE). He continues with his fervent commitment, now working with the Penn chapter of the Society for Advancement of Chicanos/Hispanics and Native Americans in Science (SACNAS), and the Penn Interdisciplinary Network for Scientists Promoting Inclusion, Retention, and Equity (INSPIRE) coalition where he plans on leading initiatives that aim to enhance diversity and student participation in science, especially students from historically marginalized groups.

“This fellowship, along with my NSF Graduate Research Fellowship, GEM Fellowship, and William Fontaine Fellowship through the University of Pennsylvania, make my research on nanoparticle-based RNA therapeutics for the reprogramming of the tumor microenvironment to treat malignancies and overcome drug resistance possible,” says Figueroa-Espada. “While my professional goal is to stay in academia and lead a research lab, my personal goal is to become whom I needed: a role model within the Latino STEM community, hoping to address many of the difficulties that impede Latino students’ success in higher education, and thanks to Toyota Motor/HSF, NSF, and GEM, I am one step closer to meeting these goals.”

New Research from Penn Engineering and MIT Shows How Nanoparticles Can Turn Off Genes in Bone Marrow

Michael Mitchell
Michael Mitchell, PhD

by Evan Lerner

Using specialized nanoparticles, researchers from Penn Engineering and the Massachusetts Institute of Technology (MIT) have developed a way to turn off specific genes in cells of bone marrow, which play an important role in producing blood cells. These particles could be tailored to help treat heart disease or to boost the yield of stem cells in patients who need stem cell transplants.

This type of genetic therapy, known as RNA interference, is usually difficult to target to organs other than the liver, where nanoparticles would tend to accumulate. The researchers were able to modify their particles in such a way that they would accumulate in the cells found in the bone marrow.

In a recent Nature Biomedical Engineering study, conducted in mice, the researchers showed that they could use this approach to improve recovery after a heart attack by inhibiting the release of bone marrow blood cells that promote inflammation and contribute to heart disease.

“If we can get these particles to hit other organs of interest, there could be a broader range of disease applications to explore, and one that we were really interested in in this paper was the bone marrow. The bone marrow is a site for hematopoiesis of blood cells, and these give rise to a whole lineage of cells that contribute to various types of diseases,” says Michael Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, one of the lead authors of the study.

Marvin Krohn-Grimberghe, a cardiologist at the Freiburg University Heart Center in Germany, and Maximilian Schloss, a research fellow at Massachusetts General Hospital (MGH), are also lead authors on the paper, which appears today in Nature Biomedical Engineering. The paper’s senior authors are Daniel Anderson, a professor of Chemical Engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and Matthias Nahrendorf, a professor of Radiology at MGH.

Mitchell’s expertise is in the design of nanoparticles and other drug delivery vehicles, engineering them to cross biological barriers that normally block foreign agents. In 2018, he received the NIH Director’s New Innovator Award to support research on delivering therapeutics to bone marrow, a key component of this new study.

The researchers have shown they can deliver nanoparticles to the bone marrow, influencing their function with RNA silencing. At top right, the bone marrow is not yet treated with particles that turn off a gene called SDF1. At bottom right, the number of neutrophils (blue) decreases, indicating that they have been released from bone marrow after treatment. At left, treatment with a control nanoparticle does not affect the number of neutrophils before and after treatment.

Read the full story at Penn Engineering Today.

Penn Bioengineering and COVID-19

A message from Penn Bioengineering Professor and Chair Ravi Radhakrishnan:

In response to the unprecedented challenges presented by the global outbreak of the novel coronavirus SARS-CoV-2, Penn Bioengineering’s faculty, students, and staff are finding innovative ways of pivoting their research and academic projects to contribute to the fight against COVID-19. Though these projects are all works in progress, I think it is vitally important to keep those in our broader communities informed of the critical contributions our people are making. Whether adapting current research to focus on COVID-19, investing time, technology, and equipment to help health care infrastructure, or creating new outreach and educational programs for students, I am incredibly proud of the way Penn Bioengineering is making a difference. I invite you to read more about our ongoing projects below.

RESEARCH

Novel Chest X-Ray Contrast

David Cormode, Associate Professor of Radiology and Bioengineering

Nanomedicine and Molecular Imaging Lab

Peter Noel, Assistant Professor of Radiology and BE Graduate Group Member

Laboratory for Advanced Computed Tomography Imaging

The Cormode and Noel labs are working to develop dark-field X-ray imaging, which may prove very helpful for COVID patients. It involves fabricating diffusers that incorporate gold nanoparticles to modify the X-ray beam. This method gives excellent images of lung structure. Chest X-ray is being used on the front lines for COVID patients, and this could potentially be an easy to implement modification of existing X-ray systems. The additional data give insight into the health state of the microstructures (alveoli) in the lung. This new contrast mechanics could be an early insight into the disease status of COVID-19 patients. For more on this research, see Cormode and Noel’s chapter in the forthcoming volume Spectral, Photon Counting Computed Tomography: Technology and Applications, edited by Katsuyuki Taguchi, Ira Blevis, and Krzysztof Iniewski (Routledge 2020).

Immunotherapy

Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering

Mitchell Lab

Mike Mitchell is working with Saar Gill (Penn Medicine) on engineering drug delivery technologies for COVID-19 mRNA vaccination. He is also developing inhalable drug delivery technologies to block COVID-19 internalization into the lungs. These new technologies are adaptations of prior research published Volume 20 of Nano Letters (“Ionizable Lipid Nanoparticle-Mediated mRNA Delivery for Human CAR T Cell Engineering” January 2020) and discussed in Volume 18 of Nature Reviews Drug Discovery (“Delivery Technologies for Cancer Immunotherapy” January 2019).

Respiratory Distress Therapy Modeling

Ravi Radhakrishnan, Professor, and Chair of Bioengineering and Professor of Chemical and Biomolecular Engineering

Radhakrishnan Lab

Computational Models for Targeting Acute Respiratory Distress Syndrome (ARDS). The severe forms of COVID-19 infections resulting in death proceeds by the propagation of the acute respiratory distress syndrome or ARDS. In ARDS, the lungs fill up with fluid preventing oxygenation and effective delivery of therapeutics through the inhalation route. To overcome this major limitation, delivery of antiinflammatory drugs through the vasculature (IV injection) is a better approach; however, the high injected dose required can lead to toxicity. A group of undergraduate and postdoctoral researchers in the Radhakrishnan Lab (Emma Glass, Christina Eng, Samaneh Farokhirad, and Sreeja Kandy) are developing a computational model that can design drug-filled nanoparticles and target them to the inflamed lung regions. The model combines different length-scales, (namely, pharmacodynamic factors at the organ scale, hydrodynamic and transport factors in the tissue scale, and nanoparticle-cell interaction at the subcellular scale), into one integrated framework. This targeted approach can significantly decrease the required dose for combating ARDS. This project is done in collaboration with Clinical Scientist Dr. Jacob Brenner, who is an attending ER Physician in Penn Medicine. This research is adapted from prior findings published in Volume 13, Issue 4 of Nanomedicine: Nanotechnology, Biology and Medicine: “Mechanisms that determine nanocarrier targeting to healthy versus inflamed lung regions” (May 2017).

Diagnostics

Sydney Shaffer, Assistant Professor of Bioengineering and Pathology and Laboratory Medicine

Syd Shaffer Lab

Arjun Raj, Professor of Bioengineering

Raj Lab for Systems Biology

David Issadore, Associate Professor of Bioengineering and Electrical and Systems Engineering

Issadore Lab

Arjun Raj, David Issadore, and Sydney Shaffer are working on developing an integrated, rapid point-of-care diagnostic for SARS-CoV-2 using single molecule RNA FISH. The platform currently in development uses sequence specific fluorescent probes that bind to the viral RNA when it is present. The fluorescent probes are detected using a iPhone compatible point-of-care reader device that determines whether the specimen is infected or uninfected. As the entire assay takes less than 10 minutes and can be performed with minimal equipment, we envision that this platform could ultimately be used for screening for active COVID19 at doctors’ offices and testing sites. Support for this project will come from a recently-announced IRM Collaborative Research Grant from the Institute of Regenerative Medicine with matching funding provided by the Departments of Bioengineering and Pathology and Laboratory Medicine in the Perelman School of Medicine (PSOM) (PI’s: Sydney Shaffer, Sara Cherry, Ophir Shalem, Arjun Raj). This research is adapted from findings published in the journal Lab on a Chip: “Multiplexed detection of viral infections using rapid in situ RNA analysis on a chip” (Issue 15, 2015). See also United States Provisional Patent Application Serial No. 14/900,494 (2014): “Methods for rapid ribonucleic acid fluorescence in situ hybridization” (Inventors: Raj A., Shaffer S.M., Issadore D.).

HEALTH CARE INFRASTRUCTURE

Penn Health-Tech Coronavirus COVID-19 Collaborations

Brian Litt, Professor of Bioengineering, Neurology, and Neurosurgery

Litt Lab

In his role as one of the faculty directors for Penn Health-Tech, Professor Brian Litt is working closely with me to facilitate all the rapid response team initiatives, and in helping to garner support the center and remove obstacles. These projects include ramping up ventilator capacity and fabrication of ventilator parts, the creation of point-of-care ultrasounds and diagnostic testing, evaluating processes of PPE decontamination, and more. Visit the Penn Health-Tech coronavirus website to learn more, get involved with an existing team, or submit a new idea.

BE Labs COVID-19 Efforts

BE Educational Labs Director Sevile Mannickarottu & Staff

BE Educational Labs staff members Dana Abulez (BE ’19, Master’s BE ’20) and Matthew Zwimpfer (MSE ’18, Master’s MSE ’19) take shifts to laser-cut face shields.

The George H. Stephenson Foundation Educational Laboratory & Bio-MakerSpace staff have donated their PPE to Penn Medicine. Two staff members (Dana Abulez, BE ’19, Master’s BE ’20 and Matthew Zwimpfer, MSE ’18, Master’s MSE ’19) took shifts to laser-cut face shields in collaboration with Penn Health-Tech. Dana and Matthew are also working with Dr. Matthew Maltese on his low-cost ventilator project (details below).

Low-Cost Ventilator

Matthew Maltese, Adjunct Professor of Medical Devices and BE Graduate Group Member

Children’s Hospital of Philadelphia Center for Injury Research and Prevention (CIRP)

Dr. Maltese is rapidly developing a low-cost ventilator that could be deployed in Penn Medicine for the expected surge, and any surge in subsequent waves. This design is currently under consideration by the FDA for Emergency Use Authorization (EUA). This example is one of several designs considered by Penn Medicine in dealing with the patient surge.

Face Shields

David F. Meaney, Solomon R. Pollack Professor of Bioengineering and Senior Associate Dean

Molecular Neuroengineering Lab

Led by David Meaney, Kevin Turner, Peter Bruno and Mark Yim, the face shield team at Penn Health-Tech is working on developing thousands of rapidly producible shields to protect and prolong the usage of Personal Protective Equipment (PPE). Learn more about Penn Health-Tech’s initiatives and apply to get involved here.

Update 4/29/20: The Penn Engineering community has sprung into action over the course of the past few weeks in response to COVID-19. Dr. Meaney shared his perspective on those efforts and the ones that will come online as the pandemic continues to unfold. Read the full post on the Penn Engineering blog.

OUTREACH & EDUCATION

Student Community Building

Yale Cohen, Professor of Otorhinolaryngology, Department of Psychology, BE Graduate Group Member, and BE Graduate Chair

Auditory Research Laboratory

Yale Cohen, and Penn Bioengineering’s Graduate Chair, is working with Penn faculty and peer institutions across the country to identify intellectually engaging and/or community-building activities for Bioengineering students. While those ideas are in progress, he has also worked with BE Department Chair Ravi Radhakrishnan and Undergraduate Chair Andrew Tsourkas to set up a dedicated Penn Bioengineering slack channel open to all Penn Bioengineering Undergrads, Master’s and Doctoral Students, and Postdocs as well as faculty and staff. It has already become an enjoyable place for the Penn BE community to connect and share ideas, articles, and funny memes.

Undergraduate Course: Biotechnology, Immunology, Vaccines and COVID-19 (ENGR 35)

Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor of Bioengineering and Chemical and Biomolecular Engineering

The Hammer Lab

This Summer Session II, Professor Dan Hammer and CBE Senior Lecturer Miriam R. Wattenbarger will teach a brand-new course introducing Penn undergraduates to a basic understanding of biological systems, immunology, viruses, and vaccines. This course will start with the fundamentals of biotechnology, and no prior knowledge of biotechnology is necessary. Some chemistry is needed to understand how biological systems work. The course will cover basic concepts in biotechnology, including DNA, RNA, the Central Dogma, proteins, recombinant DNA technology, polymerase chain reaction, DNA sequencing, the functioning of the immune system, acquired vs. innate immunity, viruses (including HIV, influenza, adenovirus, and coronavirus), gene therapy, CRISPR-Cas9 editing, drug discovery, types of pharmaceuticals (including small molecule inhibitors and monoclonal antibodies), vaccines, clinical trials. Some quantitative principles will be used to quantifying the strength of binding, calculate the dynamics of enzymes, writing and solving simple epidemiological models, methods for making and purifying drugs and vaccines. The course will end with specific case study of coronavirus pandemic, types of drugs proposed and their mechanism of action, and vaccine development.
Update 4/29/20: Read the Penn Engineering blog post on this course published April 27, 2020.

Neuromatch Conference

Konrad Kording, Penn Integrates Knowledge University Professor of Bioengineering, Neuroscience, and Computer and Information Science

Kording Lab

Dr. Kording facilitated Neuromatch 2020, a large virtual neurosciences conferences consisting of over 3,000 registrants. All of the conference talk videos are archived on the conference website and Dr. Kording has blogged about what he learned in the course of running a large  conference entirely online. Based on the success of Neuromatch 1.0, the team are now working on planning Neuromatch 2.0, which will take place in May 2020. Dr. Kording is also working on facilitating the transition of neuroscience communication into the online space, including a weekly social (#neurodrinking) with both US and EU versions.

Neuromatch Academy

Konrad Kording, Penn Integrates Knowledge University Professor of Bioengineering, Neuroscience, and Computer and Information Science

Kording Lab

Dr. Kording is working to launch the Neuromatch Academy, an open, online, 3-week intensive tutorial-based computational neuroscience training event (July 13-31, 2020). Participants from undergraduate to professors as well as industry are welcome. The Neuromatch Academy will introduce traditional and emerging computational neuroscience tools, their complementarity, and what they can tell us about the brain. A main focus is not just on using the techniques, but on understanding how they relate to biological questions. The school will be Python-based making use of Google Colab. The Academy will also include professional development / meta-science, model interpretation, and networking sessions. The goal is to give participants the computational background needed to do research in neuroscience. Interested participants can learn more and apply here.

Journal of Biomedical Engineering Call for Review Articles

Beth Winkelstein, Vice Provost for Education and Eduardo D. Glandt President’s Distinguished Professor of Bioengineering

Spine Pain Research Lab

The American Society of Medical Engineers’ (ASME) Journal of Biomechanical Engineering (JBME), of which Dr. Winkelstein is an Editor, has put out a call for review articles by trainees for a special issue of the journal. The call was made in March 2020 when many labs were ramping down, and trainees began refocusing on review articles and remote work. This call continues the JBME’s long history of supporting junior faculty and trainees and promoting their intellectual contributions during challenging times.
Update 4/29/20: CFP for the special 2021 issue here.

Are you a Penn Bioengineering community member involved in a coronavirus-related project? Let us know! Please reach out to ksas@seas.upenn.edu.

 

 

Penn Bioengineering Postdoc Rachel Riley Named Assistant Professor at Rowan University

Rachel Riley, Ph.D.

The Department of Bioengineering is proud to congratulate Postdoctoral Fellow Rachel Riley on her appointment as an Assistant Professor in Biomedical Engineering at Rowan University starting September 2020.

Originally from Matawan, NJ, Riley has been an NIH Postdoctoral Fellow in the Mitchell Lab since 2018. Her move to a faculty position at Rowan marks a return, as she received her B.S. in Civil and Environmental Engineering there in 2012. Riley went on to receive her Ph.D. in Biomedical Engineering in 2018 at the University of Delaware with Emily Day, Ph.D. before joining the lab of Michael J. Mitchell, Ph.D., Skirkanich Assistant Professor of Innovation, later that year. The Mitchell Lab’s research lies at the interface of biomaterials science, drug delivery, and cellular and molecular bioengineering to fundamentally understand and therapeutically target biological barriers.

“Rachel has had a prolific academic career at the University of Delaware and at Penn, launching several exciting research projects and mentoring the next generation of STEM researchers,” Mitchell says. “I’m very hopeful that her new position as an Assistant Professor of Biomedical Engineering at Rowan University will permit her to engineer new drug delivery technologies for women’s health applications.”

Research in the Riley Lab at Rowan will explore how nanoparticle drug delivery technologies can be engineered specifically for applications in women’s health. They will use nanoparticles as tools to study and treat gynecological cancers, fetal diseases, and pregnancy complications. Riley’s ultimate goal is to gain a fundamental understanding of how nanoparticle structure influences delivery to gynecological tissues to enable them to take an engineering approach to tackle new applications in women’s health.

Riley says that she is committed to supporting women and minorities in STEM disciplines and she looks forward to continuing collaborations with Penn and starting new collaborations with researchers at Cooper Medical School at Rowan University (CMSRU). Congratulations, Dr. Riley!

Penn Nanoparticles are Less Toxic to T Cells Engineered for Cancer Immunotherapy

An artist’s illustration of nanoparticles transporting mRNA into a T cell (blue), allowing the latter to express surface receptors that recognize cancer cells (red). (Credit: Ryan Allen, Second Bay Studios)

New cancer immunotherapies involve extracting a patient’s T cells and genetically engineering them so they will recognize and attack tumors. This type of therapy is not without challenges, however. Engineering a patient’s T cells is laborious and expensive. And when successful, the alterations to the immune system immediately make patients very sick for a short period of time, with symptoms including fever, nausea and neurological effects.

Now, Penn researchers have demonstrated a new engineering technique that, because it is less toxic to the T cells, could enable a different mechanism for altering the way they recognize cancer, and could have fewer side effects for patients.

The technique involves ferrying messenger RNA (mRNA) across the T cell’s membrane via a lipid-based nanoparticle, rather than using a modified HIV virus to rewrite the cell’s DNA. Using the former approach would be preferable, as it only confers a temporary change to the patient’s immune system, but the current standard method for getting mRNA past the cell membrane can be too toxic to use on the limited number of T cells that can be extracted from a patient.

Michael Mitchell, Margaret Billingsley, and Carl June

The researchers demonstrated their technique in a study published in the journal Nano Letters. It was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation of bioengineering in the School of Engineering and Applied Science, and Margaret Billingsley, a graduate student in his lab.

They collaborated with one of the pioneers of CAR T therapy: Carl June, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and the director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine.

Read more at Penn Engineering blog.

Michael Mitchell Receives Chinese Association for Biomaterials Young Investigator Award

Michael Mitchell, Ph.D.

Michael Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering at the University of Pennsylvania, has received a Young Investigator Award from the Chinese Association for Biomaterials.

Mitchell received the Young Investigator Award at the Biomaterials Science Excellence and Technology Translation Workshop in collaboration with the Society for Biomaterials at the 2019 Annual Meeting in Seattle, Washington.

According to the Chinese Association for Biomaterials, “The CAB Young/Mid-Career Investigator Awards recognize the individuals who have successfully demonstrated significant achievements in the field of biomaterials research.”

The Chinese Association for Biomaterials was founded in 2015 at the Society for Biomaterials Annual Meeting. It is a non-profit professional organization that aims to facilitate exchange of research ideas and to promote collaboration among scientists in the fields of biomaterials research.

Mitchell joined the Department of Bioengineering at Penn in 2018 as Skirkanich Assistant Professor of Innovation. Previously, he was an NIH Ruth L. Kirschstein Postdoctoral Fellow with Institute Professor Robert Langer at the Koch Institute for Integrative Cancer Research at MIT. His research interests include biomaterials, drug delivery, and cellular and molecular bioengineering for applications in cancer research, immunotherapy, and gene therapy. Since joining Penn in 2018, Mitchell has received the NIH Director’s New Innovator Award, the Burroughs Wellcome Fund Career Award at the Scientific Interface, a Rising Star Award from the Biomedical Engineering Society, and the T. Nagai Award from the Controlled Release Society.

Originally posted on the Penn Engineering Medium blog.

Michael Mitchell Elected Society for Biomaterials Drug Delivery Chair

by Sophie Burkholder

 

Michael Mitchell, Ph.D., Skirkanich Assistant Professor of Innovation in the Department of Bioengineering at the University of Pennsylvania, was elected Chair of the Drug Delivery Special Interest Group for the Society for Biomaterials at the 2019 Annual Meeting in Seattle, Washington. According to the Society for Biomaterials website:

The Drug Delivery Special Interest Group will deal with the science and technology of controlled release of active agents from delivery systems. Controlled drug release is achieved by the use of diffusion, chemical reactions, dissolutions or osmosis, used either singly or in combination. While the vast majority of such delivery devices are based on polymers, controlled release can also be achieved by the use of mechanical pumps. In a broader sense, controlled release also involves control over the site of action of the active agent, using the active agent using pro-drugs, targetable water soluble polymers or various microparticulate systems. Relevant aspects of toxicology, bioavailability, pharmacokinetics, and biocompatibility are also included.

The Society for Biomaterials is an interdisciplinary organization comprised of academic, industry, health care, and governmental professionals dedicated to promoting advancements in all aspects of biomaterial science and engineering, education, and professional standards to enhance human health and quality of life. The Society for Biomaterials was established in 1974, and is the oldest scientific organization in the field of biomaterials.

Michael Mitchell, Ph.D.

Mitchell joined the Department of Bioengineering at Penn in 2018 as Skirkanich Assistant Professor of Innovation. Previously, he was an NIH Ruth L. Kirschstein Postdoctoral Fellow with Institute Professor Robert Langer at the Koch Institute for Integrative Cancer Research at MIT. His research interests include biomaterials, drug delivery, and cellular and molecular bioengineering for applications in cancer research, immunotherapy, and gene therapy. Since joining Penn in 2018, Mitchell has received the NIH Director’s New Innovator Award, the Burroughs Wellcome Fund Career Award at the Scientific Interface, a Rising Star Award from the Biomedical Engineering Society, and the T. Nagai Award from the Controlled Release Society.

Mitchell’s new role as the Chair of the SFB’s Drug Delivery Special Interest Group will allow him to lead conversations across academia on the future of drug delivery as it relates to biomaterials. With his fellow officers, Mitchell will help spread knowledge about the field of controlled drug release by hosting research forums, helping to publish news and activities of the SFB in Biomaterials Forum, and foster connections and mentorship among members of his and other Special Interest Groups. We can’t wait to see where Mitchell’s leadership will help take the community of research on areas like toxicology, pharmacokinetics, and biocompatibility next!

BE’s Michael Mitchell Wins Controlled Release Society T. Nagai Award

Michael Mitchell, Ph.D.

Michael Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is the recipient of the Controlled Release Society (CRS) 2019 T. Nagai Postdoctoral Research Achievement Award, which comes with a $3,000 honorarium.

According to the CRS website, “The Controlled Release Society T. Nagai Postdoctoral Research Achievement Award has been established to recognize an individual postdoctoral candidate who has recently completed outstanding postdoctoral research in controlled release science and technology, and the postdoc’s advisor who played an integral role in those achievements.”

Mitchell and his postdoctoral advisor at MIT, Robert Langer, will receive the award at the 2019 CRS annual meeting this July in Valencia, Spain.

The sole recipient of this award, Mitchell was recognized for his work on engineering controlled release technologies for cancer gene therapy and immunotherapy. Mitchell focuses on improving the way drugs are delivered within the body by combining approaches from engineering, biology, machine learning, and data science to better target diseased cells. Mitchell’s work helps to lay the foundation for a new class of therapeutic strategies against hematologic cancers such as multiple myeloma and leukemia.

For this research, Mitchell also received the Burroughs Wellcome Fund Career Award at the Scientific Interface in 2016, the NIH Director’s New Innovator Award in 2018, and a Rising Star Award in Cellular and Molecular Bioengineering from the Biomedical Engineering Society in 2019. He joined the Penn faculty in January 2018 after completing an NIH NCI postdoctoral fellowship at the Koch Institute for Integrative Cancer Research at MIT.

Originally posted on the Penn Engineering Medium blog. Media contacts Evan Lerner.