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Federal Funding Fueled Growth of Wistar Science in 2018

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Feb. 11, 2019) — The Wistar Institute announces that it was awarded more than $16M in federal research funds in support of its groundbreaking research in cancer, immunology and infectious diseases. Highlights from select awarded grants include:

  • Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program, was awarded a grant for $2,232,500 over five years. This grant will support a project to study the role of particular genomic regulatory sequences termed enhancers and the Integrator transcription complex during maturation of monocytes.
  • Kazuko Nishikura, Ph.D., professor in the Gene Expression & Regulation Program, was granted a four-year renewal of a grant for $1,917,880 that funds research on the functions of the ADAR1 enzyme that her lab discovered and characterized. This grant has been continuously renewed for 26 years.
  • Paul Lieberman, Ph.D., professor and leader of the Gene Expression & Regulation Program and Hilary Koprowski, M.D., Endowed Professor, was granted a five-year renewal for $1,904,515 of a grant that supports research on the molecular mechanisms of cancers associated with Epstein-­Barr Virus long-term latent infections. This grant has provided continuous support for this project for 16 years.
  • The Institute received a $398,418 supplement to its Cancer Center Support Grant from the National Cancer Institute. This supplement will provide funds for two years to Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, to support his innovative research to understand the mechanisms that drive cancer onset in HIV-infected individuals by dissecting the role of carbohydrate structures (glycans) present in the host immune environment.
    Several Wistar scientists were co-principal investigators in multi-laboratory collaborative grants or received subawards as part of larger grants to other institutions.
  • Joseph Salvino, Ph.D., professor in the Molecular & Cellular Oncogenesis Program, received sub-contracts from two grants with Drexel University and Case Western Reserve University. The first grant will support optimization of a novel anti-HIV compound through medicinal chemistry approaches; the second grant will support the development of novel compounds to target metabolic vulnerabilities of pancreatic cancer. Salvino will receive funds for $1,030,885 and $325,465, respectively, over five years.
  • Ashani Weeraratna, Ph.D., Ira Brind Professor Professor and co-leader of the Immunology, Microenvironment & Metastasis Program, is one of the principal investigators in a multi-laboratory cooperative grant awarded to the University of Pennsylvania. The research team will investigate how some rare cells within a tumor are able to evade the effects of the therapy, which may have a potential clinical impact on melanoma treatment. Weeraratna received funds for $1,038,685 over five years.
  • Andrew Hu, Ph.D., associate professor in the Immunology, Microenvironment & Metastasis Program, received a $745,308 sub-award from a larger grant to the Medical University of South Carolina. This four-year award will support research on graft versus host disease after hematopoietic stem cell transplantation in leukemia.
  • Luis J. Montaner, D.V.M., D.Phil., vice president of Scientific Operations, director of the HIV-1 Immunopathogenesis Laboratory and Herbert Kean, M.D., Family Professor, is a co-investigator on a grant to Yale University and received a sub-award for $475,712 over five years. The research project focuses on the mechanisms of HIV-1-driven proliferation of infected CD4+ T cells that contributes to viral latency and hampers the HIV eradication efforts.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Engineered DNA Vaccine Protects Against Emerging Mayaro Virus Infection

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Feb. 7, 2019) — A novel, synthetic DNA vaccine developed at The Wistar Institute induces protective immunity against Mayaro virus (MAYV), a mosquito-borne infection endemic to South America, that has the potential to become a global emerging viral threat. Study results were published in PLOS Neglected Tropical Diseases.

Since its discovery in 1954, MAYV infections have been confined to the heavily forested areas of Trinidad and Tobago and the neighboring regions of South America. However, a reported case of MAYV infection in Haiti in 2015 and laboratory evidence suggest that multiple mosquito species can transmit MAYV, highlighting the potential for further uncontrolled expansion of MAYV into tropical regions of the Caribbean and Central and South America.

“Although MAYV was discovered a long time ago and can cause severe health complications, it remains a neglected disease and is understudied,” said Kar Muthumani, Ph.D., director of the Laboratory of Emerging Infectious Diseases at The Wistar Institute and assistant professor in Wistar’s Vaccine & Immunotherapy Center. “The potential for this virus to spread beyond its historical geographic range, as Zika virus did a few years ago, makes the creation of an effective immunization strategy even more pressing.”

Similar to infections caused by dengue or chikungunya viruses, MAYV infection causes fever, rash, headache, nausea, and vomiting for prolonged periods in many people and can lead to persistent and debilitating muscle and joint pain in some patients. There are no approved treatments or preventative medicines for Mayaro fever.

In the new study, Muthumani and colleagues created a novel synthetic DNA vaccine targeting MAYV envelope (E) protein isolated from the major circulating strains of MAYV (“scMAYV-E”). The vaccine’s unique design accounts for the natural genetic variability of this major viral surface antigen, and it was optimized to improve its expression in vivo. The scMAYV-E DNA vaccine was administered by intramuscular injection followed by electroporation, pulses of electricity designed to make cells more permeable to foreign DNA and enhance vaccine uptake, which allows for dose-sparing.

Immunization with scMAYV-E induced potent protective and MAYV-specific immune responses in mice, including both MAYV infection-neutralizing antibodies as well as cellular responses to multiple regions of MAYV-E. Importantly, the scMAYV-E vaccine provided complete protection from death and clinical signs of infection in a MAYV-challenge mouse model.

“The robust immunogenicity of the scMAYV-E vaccine demonstrated here supports the need for further testing of this vaccine as a viable means to halt the spread of this virus and protect individuals at risk from MAYV disease,” added Muthumani. “DNA vaccines have a remarkable safety record in numerous clinical trials, can be designed and manufactured readily, and can be distributed cost-effectively, making them an important tool for combating emerging infectious diseases like MAYV especially in resource-poor settings, where they often arise.”

Co-authors: Hyeree Choi (first author), Sagar B. Kudchodkar, Emma L. Reuschel, Kanika Asija, Piyush Borole, Michelle Ho, Krzysztof Wojtakand, and David B. Weiner from The Wistar Institute; Charles Reed, Stephanie Ramos, Joseph Kim, and Laurent Humeau from Inovio Pharmaceuticals, Inc.; Nathen E. Bopp, Patricia V. Aguilar, and Scott C. Weaver from University of Texas Medical Branch, Galveston; and Pablo Tebas from University of Pennsylvania.

Work supported by: Inovio Pharmaceuticals, Inc.

Publication information: Protective immunity by an engineered DNA Vaccine for Mayaro Virus, PLOS Neglected Tropical Diseases (2019). Advanced online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Cullinan Oncology to Develop Novel EBNA1 Inhibitor Discovered by The Wistar Institute

Written by The Wistar Institute on . Posted in Press Releases.

CAMBRIDGE, MA and PHILADELPHIA — January 30, 2019 — Cullinan Oncology, LLC and The Wistar Institute today announced an agreement to accelerate the development of VK-2019, a novel EBNA1 (Epstein-Barr Nuclear Antigen 1) inhibitor discovered by The Wistar Institute.

VK-2019 will be developed by Cullinan Apollo, a company formed and managed by Cullinan Oncology LLC. Under the terms of the agreement, The Wistar Institute has granted an exclusive worldwide license for the development and commercialization of the EBNA1 inhibitor to Cullinan Apollo. Wistar has received an up-front license fee and an equity interest in Cullinan Apollo, with the potential to receive additional downstream milestones and royalty payments as the asset progresses.

“We look forward to advancing this highly novel, first-in-class asset into the clinic over the coming weeks,” said Leigh Zawel, CSO, Small Molecules at Cullinan Oncology, LLC. “The Wistar scientists have spent nearly a decade developing this molecule, and we appreciate their confidence in our ability to successfully develop this EBNA1 inhibitor.”

EBV (Epstein-Barr Virus), a well-established driver of various cancers, is critically reliant on the viral DNA-binding factor EBNA1 for viral genome maintenance. This new compound potently inhibits EBNA1 function. In preclinical models of EBV-associated cancer, it eliminated EBV, resulting in tumor growth inhibition. Development of this compound was largely supported by an investment of over U.S. $10 million from Wellcome, a biomedical research charity based in the United Kingdom.

“We are excited to work with the Cullinan Apollo team to embark on the next phase of clinical development of our lead therapeutic candidate for EBV-associated cancers,” said Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor, professor and leader of the Gene Expression and Regulation Program, and director of the Center for Chemical Biology and Translational Medicine at The Wistar Institute. “This drug is exemplary of the results of the hard work of my lab – most notably Dr. Troy Messick – together with our committed collaborators at Fox Chase Chemical Diversity Center, Inc. and invaluable input from Wellcome and its advisors. We need exceptional partners to work with us to move our discoveries forward, and this is one example of that.”

About Cullinan Oncology
Cullinan Oncology was formed to develop a diversified portfolio of highly promising single asset oncology opportunities through both internal and external means and to do so in a unique, cost-efficient model that leverages a central management team and shared services model to drive speed and efficiency. For additional information, please visit www.cullinanoncology.com.

About The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. www.wistar.org.

About Wellcome
Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation.

Media Contacts:

For Cullinan:
Matt Burke
mburke@cullinanoncology.com
+1 603.315.0618

For Wistar:
Tara Yates
tyates@wistar.org
+1 215.898.3826

Scientists of Tomorrow: Carver High School Students Visit Wistar

Written by The Wistar Institute on . Posted in Featured News.

Scientists at The Wistar Institute had the pleasure of hosting 30 young ladies from George Washington Carver High School of Engineering and Science who take part in the Women of Tomorrow (WOT) Mentor & Scholarship Program. Their visit kicked off with a microscopy introduction by James Hayden, Wistar Imaging Facility managing director, showing how scientists use dynamic imaging of tissues, cells and cellular structures in their work to move cancer and infectious disease research forward. The group then toured the Nikon Small World exhibit currently on view at the Institute.

Next, they visited the lab of immunologist and synthetic DNA vaccine expert Dr. David Weiner, where Drs. Emma Reuschel, Ami Patel and Alfredo Perales Puchalt discussed their research specialties and talked about the progress they’re making creating DNA vaccines for cancer and emerging infectious diseases.

Over lunch, the ladies were then engaged in a conversation focused on opportunities for scientific education and training at Wistar. Drs. Brian Keith, dean of Biomedical Research, and Anita Pepper, vice president of Institutional Advancement, and Jessica Palmer, education program coordinator, also spoke to their experiences in higher education, providing insight and advice on career paths in the biomedical sciences, including research, education, administration, and philanthropy.

CBS3 Philly TV anchor and WoT mentor Stephanie Stahl previewed the Nikon Small World exhibit, interviewing Wistar’s James Hayden and including sound bites from visiting Carver High School students on tour.

Induction of Potent Anticancer Immunity Through Rapid Tumor Antigen Identification and Conversion to Personalized Synthetic DNA Vaccines

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Jan. 24, 2019) — Wistar scientists and collaborators demonstrated the utility of an optimized synthetic DNA vaccine platform for rapidly inducing immunity against unique combinations of tumor neoantigens. These results reveal a direct pathway to effectively tackling the tumor variability that presents enormous challenges for the development of effective immune strategies.

This study, published online in Cancer Immunology Research, advanced the techniques for rapidly screening neoantigens from patients and designing vaccine cassettes that allow for simple expression of dozens of antigens in a single formulation. This personalized approach resulted in a much higher CD8+ T-cell immunity than that achievable through other approaches. It also provided a simple, consistent and potent system that was effective at killing tumor cells, slowing tumor growth and profoundly delaying or preventing tumor progression in preclinical models of lung and ovarian cancer, according to the study.

During disease progression, cancer cells accumulate a vast number of genetic mutations. This process generates novel antigens, called neoantigens, that are not present in normal cells and can, therefore, be a target for the immune response. The major goals for an effective individualized treatment of cancer patients would be to rapidly identify the unique set of neoantigens expressed on a patient-specific basis and use this information to build a matched diverse collection of antigens into a vaccine that can be simply and repeatedly administered to that patient to generate CD8+ killer T cells.

“Neoantigens are a highly promising field of investigation,” said corresponding author David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. “Prior strategies were limited in several aspects, including the number of neoantigens they could encode in one vaccine and the speed with which the vaccine could be generated. Most of these prior vaccines generated a lower percentage of CD8 killer T cells, which are the ‘Navy SEALs’ of the immune system that can hunt and destroy the patient’s specific cancer.”

In this study, Weiner and colleagues utilized a rapid approach to identify new antigens and their degree of expression in the tumors and then used advanced molecular tools to “sew” dozens of the identified neoantigens into cassettes that were optimized for expression and processing in a way that would result in high presentation to the immune system.

“The speed of development of previous approaches was considerably slower,” added Weiner. “We have developed a simple format for rapid development of patient-specific cancer vaccines targeting antigens derived from their tumors and provided a proof of principle for this novel approach.”

The team started by sequencing tumors from three different mouse models of lung and ovarian cancers and identifying the mutations that generate unique neo-epitopes, or bits of proteins that are altered or not present in the corresponding non-mutant molecule. They then designed DNA plasmids, each encoding a string of 12 of these epitopes, for a total of seven DNA vaccines and 84 neo-epitopes.

These DNA vaccines were delivered in mice using controlled CELLECTRA® electroporation in order to enhance their potency. In contrast to prior approaches, in this study 75% of the epitopes driven by the vaccine were targeted by CD8+ T cells. This illustrates that platform limitations, synthetic DNA design and specifics of delivery can all impact the immune response outcome.

Importantly, T cells isolated from the immunized mice and co-cultured with tumor cells only attacked and killed cells from their corresponding tumor type, demonstrating the high specificity of their cytotoxic activity. Researchers tested the vaccines in tumor-bearing mice and observed a profound delay in tumor progression and a significant increase in survival after vaccination.

“Because of the dynamic nature of cancer mutations, which tend to be passenger mutations, targeting multiple neoantigens simultaneously is critical for the success of immunotherapy as it reduces the likelihood of tumor escape,” said Alfredo Perales Puchalt, M.D., Ph.D., postdoctoral fellow in the Weiner Lab and co-first author on the study. “Our promising preclinical results warrant further development of this personalized medicine approach.”

Co-authors: Elizabeth K. Duperret (co-first author) and Regina Stoltz from The Wistar Institute; Hiranjith G. H., Nitin Mandloi and Amitabha Chaudhuri from MedGenome Inc.; and James Barlow and Niranjan Y. Sardesai from Inovio Pharmaceuticals and Geneos Therapeutics.

Work supported by: National Institutes of Health grants F32 CA213795 and SPORE P50CA174523 to University of Pennsylvania and The Wistar Institute. Core support for Wistar was provided by the Cancer Center Support Grant P30 CA010815. Additional funding was provided by the W.W. Smith Charitable Trust, the Basser Foundation, a grant from Inovio Pharmaceuticals, and internal research support from Geneos Therapeutics.

Publication information: Synthetic DNA multi-neoantigen vaccine drives predominately MHC class I CD8+ T cell mediated effector immunity impacting tumor challenge, Cancer Immunology Research (2018). Advanced online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Beauty Beneath the Lens: Nikon Small World Exhibit at Wistar

Written by The Wistar Institute on . Posted in Featured News.

The opening reception of Nikon Small World, the popular microphotography exhibit hosted every year at Wistar for the past 16 years, reminded us about the beauty hidden within the complexity of life.

Guests enjoyed a first view of the gallery and a speaker program that represented different perspectives — and eyes — from behind the camera and microscope, and in front of the final images.

For Alan Taylor, senior editor at The Atlantic and a judge for the Nikon Small World international competition, photography is the bread and butter of his day-to-day work. He looks at thousands of pictures each day to tell the stories of what’s happening in the world. During his talk, he walked the audience through a sequence of compelling images to explain how beauty, and the stories being it, captures his attention as an editor and a judge for the competition.

The first image was the famous 1968 ‘Earthrise’ photo taken by the Apollo 8 crew. As Taylor described it, it is the first look at ourselves from space. This photo was made possible by the work of thousands of scientists and engineers, and is the perfect example of how a wealth of scientific information allows for a moment of beauty to be forever captured for humankind to enjoy. Next was a picture of the universe taken by the Hubble Telescope, in which Earth is visible as just a minuscule bright dot, immediately followed by a photo that captured a single atom suspended in electric fields, also visible as a tiny dot. These two photos, juxtaposed, perfectly described how a single dot can epitomize our entire world and all we’ve ever known about it as well as the smallest constituent of matter.

Taylor said he is drawn to images that evoke emotions and make viewers feel like they were transported. He picks images that illustrate connections between human beings and evoke empathy for the dignity of every human condition, such as a famous photo taken of a Syrian man listening to records and smoking his pipe in his bombed-out bedroom.

Patterns and repetition are preferred themes, exemplified in a photo of the microscopic scales on a butterfly wing only visible through electron microscopy and an aerial view of a gigantic pile of yellow bicycles abandoned in a field in China.

Images are powerful when they are able to tell stories. A self-proclaimed science fan, Taylor said that scientific imagery, in particular, brings people along on their own journey of discovery.

Norm Barker, professor of pathology and art as applied to medicine at Johns Hopkins School of Medicine and a veteran winner in the Nikon Small World competition, spoke about his winning image of a human tear, how it came to be and how something as simple as a human tear can show a beautiful pattern when looked at and photographed in the right conditions. Barker said scientific imagery deserves to be on display in fine art museums and stressed how this exhibit motivates the young generations to become interested in the sciences.

Michael Much, winner of an image of distinction, is a retired microscopist who dedicates his time and expertise to thoroughly extract images from specimens that attract his curiosity. His interests range from computer chips to tissue sections, from pharmaceuticals to insects, which he captures when they fly into his garage window screen and end up under his microscopic lens.

Wistar’s James E. Hayden, RBP, FBCA, managing director of the Imaging Facility and also a regular contributor to Nikon Small World, closed the program and discussed his image of distinction, the fibers of a dandelion puff, which he generated while experimenting with a new Wistar microscope. Hayden also discussed the beautiful images of insidious diseases seen at Wistar, all in the pursuit of biomedical research discovery at the intersection of science and art.

For an opportunity to be delighted by the beauty and learn the stories behind these images, pay a visit to see the fascinating photographs of Nikon Small World, on view at Wistar during business hours now through April 5 from 9 am until 5 pm.

To see the gallery of winning images, including Honorable Mentions and Images of Distinction, visit nikonsmallworld.com.

Nikon Small World Opening Night Reception

Synthetic DNA’s Role in Advancing Next Generation Checkpoint Inhibitors for Cancer Immunotherapy

Written by The Wistar Institute on . Posted in Featured News.

An innovative and original synthetic DNA platform created by Dr. David Weiner and team at Wistar’s Vaccine & Immunotherapy Center continues to make great strides in cancer immunotherapy.

Monoclonal antibody (mAb) therapy is one of the most successful approaches for cancer treatment, representing a specific method to zero in on a defined molecular target in the tumor. Antibody technology is central for cancer immunotherapy, which relies on the ability of mAbs to take the breaks off our immune system by inhibiting immune checkpoint molecules. Traditional mAbs are created from cell lines in highly sterile manufacturing plants and are difficult and expensive to make. The Weiner Lab has overcome challenges associated with therapeutic antibody production by developing a novel molecular platform that delivers DNA instructions to a patient that allow the patient’s body to become the production site of its own highly personalized mAbs.

DNA-encoded monoclonal antibodies (DMAbs) are the resulting products of DNA-delivered instructions for the body to make monoclonal antibodies using its own protein manufacturing machinery. The Weiner Lab is advancing this novel technology for cancer and infectious disease immunotherapy.

In a study that was recently published in the journal Oncotarget, they created synthetic DNA-encoded checkpoint inhibitor antibodies targeting the PD-1 checkpoint molecule. Preclinical data presented in this study demonstrated that a single injection of the highly optimized DMAb versions of PD-1 checkpoint inhibitors is sufficient to achieve a robust expression that lasts for several months in mice.

These results reinforce the findings of a previous study, published a few months ago in the journal Cancer Research, in which Weiner and colleagues developed synthetic DNA-encoded checkpoint inhibitor antibodies targeting CTLA-4, another important cancer checkpoint molecule that blocks anti-cancer immunity.

References:

Simplifying checkpoint inhibitor delivery through in vivo generation of synthetic DNA-encoded monoclonal antibodies (DMAbs), Perales-Puchalt A. et al., Oncotarget, 2019

Synthetic DNA-encoded monoclonal antibody delivery of anti-CTLA-4 antibodies induces tumor shrinkage in vivo, Duperret E.K. et al., Cancer Research, 2018

The Opportunity Journey: Innovative Program Prepares Next Generation Scientists

Written by The Wistar Institute on . Posted in Featured News.

According to Brian Keith, Ph.D., Wistar dean of Biomedical Studies, basic cancer research unravels the complex cellular and genetic mechanisms that underlie disease, and spurs the development of new, rationally designed therapies to ultimately improve patient outcomes. “We strive to help our students broaden their perspective and expand the diversity of viewpoints to comprehend how these incredibly complex processes work,” said Keith.

In the first year of the Program, students take graduate classes and serve as teaching assistants in undergraduate courses, while performing rotations in prospective thesis research labs at Wistar or USciences. In the second year, students take additional courses on basic cancer biology, molecular screening and translational research at Wistar, and begin their own laboratory research projects that will lead to their Ph.D. degree.

“Our program targets outstanding students that might not have the opportunity to train in some other highly competitive Ph.D. programs, but share a great drive, motivation and have extensive experience so that they can hit the ground running,” said Keith.

Many of the students in the Wistar/USciences Ph.D. Program have spent time working as lab technicians after college and have acquired critical skills while in the workforce. Joseph Zundell is one of those promising students. He works as a predoctoral researcher in the lab of Rugang Zhang, Ph.D., deputy director of Wistar’s Cancer Center and professor and co-leader of the Gene Expression & Regulation Program. Next year, he will defend his thesis and then spend three to four years as a postdoctoral fellow in a new lab and city, with his eye set on finally running his own lab.

“The Program is a great experience. It was demanding to teach and juggle a full class load, but this was good practice to make me a well-rounded scientist and contribute to my end goal,” said Zundell. “I know this Program and the cachet of working at The Wistar Institute will open up many opportunities.”

Each of the students who have already completed the Wistar/USciences Ph.D. Program in cancer biology have published first-author papers in leading journals, including Nature, PNAS and Cancer Discovery, and many have received prestigious awards, fellowships, and grants, including a coveted F99/K00 Predoctoral to Postdoctoral Transition Award from the National Institutes of Health.

WISTAR’S EDUCATIONAL MISSION
Wistar has long believed real world know-how through practice is a teaching keystone. Our principal investigators are global leaders in basic biomedical research in cancer and infectious disease, as well as mentors to accomplished predoctoral and postdoctoral fellows that will go on to lead successful labs or take top scientific positions in the pharmaceutical or life sciences industry.

The concept of real-world experience is central to Wistar’s education and training philosophy and has served its programs well for years now:

  • the High School Summer Fellowship in Biomedical Research, an immersive summer course where top high school students carry out bench research under the guidance of a dedicated mentor;
  • the Biomedical Technician Training (BTT) Program through which a class of Community College of Philadelphia students receive extensive lab training to become generalist technicians within the burgeoning life sciences industry; and
  • Wistar’s first-in-country, state credentialed, Biomedical Research Technician (BRT) Apprenticeship, which offers additional training to BTT graduates to become specialized life sciences technicians with experience working in multiple labs.

Learn more: wistar.org/education-training

Using Spider Venom to Make New Therapeutics for Central Nervous  System Disorders

Written by The Wistar Institute on . Posted in Featured News.

Wistar’s Joseph Salvino, Ph.D., medicinal chemist and professor in the Molecular & Cellular Oncogenesis Program, and scientific director of the Molecular Screening & Protein Expression facility at Wistar, is currently developing a new potential therapy based on the venom of the Parawixia striata spider. This colony spider lives socially in a cluster of hundreds of spiders high up in tree canopies throughout South America, including Brazil. It uses its venom to paralyze insect prey.

“This project is different from the bulk of my work, because spider venom is a natural product made from a very complex cocktail of proteins, peptides, salts, and other molecules,” said Salvino. “Synthesizing natural products is extremely complex.”

The unique opportunity for Salvino to work with spider venom originated through a collaboration with colleague Andréia Mortensen, Ph.D., assistant research professor in the Pharmacology & Physiology Department at Drexel University College of Medicine, whose Ph.D. thesis centered on animal venoms and how they modulate the central nervous system.

“I was working towards a Ph.D. in biochemistry at Ribeirão Preto School of Medicine at the University of São Paulo, Brazil,” said Mortensen. “My advisor was interested in animal venoms of all kinds and we found interesting components of these venoms that would regulate the central nervous system of mammals. One of these is glutamate, which is also the main excitatory neurotransmitter in our brain.”

Mortensen studied the effects of venom in animal studies and found one component increased the activity of glutamate transporters. 

“This venom component helps transporters remove excess glutamate and therefore is neuroprotective in conditions like traumatic brain injury, where excess glutamate causes too much excitation and kills brain cells,” she said.

Mortensen, Salvino and colleagues are interested in treating other disorders and diseases of the central nervous system such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS (Amyotrophic Lateral Sclerosis), epilepsy, stroke, and neuropathic pain, where there is a disfunction in glutamate concentrations or an over-release of glutamate that results in toxicity. 
Previous work had shown that there were structures in venom that would target glutamatergic channels and receptors in our brain. “But there could be much more—transporters are other structures in our brain that we thought venom could modulate, but we didn’t know exactly how,” said Mortensen. 

It was the 90s in Brazil with a rich source of spiders in the vicinity of the university. What started as an exploration became a major find in the components of venom in these spiders. Spider venom became Mortensen’s life’s work. She continued collecting spiders, extracting venom and characterizing it with high profile liquid chromatographs that break down venom into several components. Then she came to the United States to access technology specialized in glutamate transporters and carried out selectivity studies and finally found the one active component of the venom she was targeting.

“I was at Oregon Health Science University (OHSU) for six months in the middle of my Ph.D. on an internship as an exchange student,” said Mortensen. “But I came back to do my postdoctoral fellowship at OHSU. At that point, I changed my interest to understanding glutamate transporters: Nowadays my lab at Drexel is a ‘glutamate transporter’ lab and we use the venom to develop synthetic components, which has become a collaboration of more than six years with Dr. Salvino, who can take my work further. Our collaboration came at the right time because working with natural products is very tricky.”

Salvino spent more than 20 years in drug discovery at biotechnology and pharmaceutical industries before he became a professor in the Department of Pharmacology and Physiology at Drexel and then came to Wistar. He works closely with many scientists to help identify novel small molecule lead compounds that could become future drugs. Exploring spider venom for possible drug targets was a welcome challenge. 

“Glutamate is an important neurotransmitter,” said Salvino. “You need it, but at high concentrations it causes glutamate excitotoxicity. In diseases where you have this excess glutamate effect, it causes neurodegeneration or pain.”

Devi Ashok, Ph.D., another key player in this project, was a graduate student in chemistry and worked as a postdoctoral fellow at the University of Guelph, in Canada. She then enrolled in the Master’s program in Drug Discovery & Development at Drexel in 2015 with the hope of working in the pharmaceutical industry. “I worked with Dr. Salvino for two summers and came up with the first lead compound derived from spider venom,” said Ashok. “The project was very interesting and rewarding. I always wanted to work in pharma and this turned into a good platform to launch my career ambition.” Ashok was involved in the synthesis of analogues which had the potential to boost activity of glutamate transporters in the brain.

“It was so exciting to be in the lab making a compound that would be tested in real time by a fellow student just across the corridor,” said Ashok. “Getting that immediate feedback was fantastic and led me to think about what experiments I should do next, what changes I should make to get a more positive result and what direction I should try.”

Ashok’s compound was definitely neuroprotective. “It protects against neurodegeneration induced in a traumatic brain injury,” said Salvino. “It stimulates the transporters to remove excess glutamate, is protective and shields against neurodegeneration.”

Nick Anastasi, a University of Pittsburgh student, interned in Wistar’s Salvino Lab in the summer of 2017. 

“My primary job was synthesizing new chemical compounds of Ashok’s advanced lead,” said Anastasi. “We had molecules we knew were active and performed in a certain way, and I was making modifications to them to improve activity, which it ultimately ended up doing.” 
Because of his experience in the Salvino Lab, Anastasi was inspired to change direction in his education and focus on bioengineering.

“I’m interested in going into the biotech industry after having worked at Wistar and seeing how Dr. Salvino forged his path,” said Anastasi. “The industry is very interesting and rewarding. It’s an upfront satisfaction where, once you complete your work and you have your lead, you can transfer it to partners that will develop and commercialize a product that helps people. Hopefully the scientific advancement I helped make at Wistar will be able to cure people and have multiple applications.” The satisfaction of running reactions, making chemicals and creating molecules is payoff in itself. 

“It’s not uncommon to find researchers in the lab throughout the day because they’re running reactions and very into what they’re doing,” said Salvino. “What’s cool with Devi and Nick is they were able to make compounds that had great activity. They could see it, and I could see that spark.”

Next steps are to realize the compound’s potential by securing funding and garnering interest from industry. But the crux of their success lies in exploration, determination and collaboration.
“We’d love to see this eventually evaluated in clinical trials to confirm this approach is useful,” said Salvino. “We’re the only ones with a molecule like this and it’s eluded the industry for years. We would love to get this into clinic.” 

GLOSSARY

Glutamate  
The main excitatory neurotransmitter in the central nervous system, also involved in memory and learning. In the synapses, it’s released by nerve cells and binds with specific receptors that send a signal down to the muscles or brain, but too much of it causes overstimulation.

Salvino says: “It’s like an electrical cable—you put too much voltage to it and it burns up and then neuronal death happens.”

Glutamate Transporters 
Proteins that play an important role regulating the amount of glutamate in the extracellular space in the brain, preventing excessive stimulation of glutamate receptors.

Salvino says: “Transporters sit like a vacuum cleaner and suck out glutamate from the synaptic space. As soon as it’s sucked out, it’s converted to glutamine and becomes inactive. Transporters are key to keeping the balance. Think of any electrical circuit or battery—too much electricity going across will short-circuit.”

First-in-class DNA-encoded Monoclonal Antibody Therapy Rapidly Advances into the Clinic

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (January 8, 2019) — The Wistar Institute, along with partners Penn Medicine and Inovio Pharmaceuticals, Inc. (NASDAQ:INO), announce that the FDA has approved the initiation of a first-in-human clinical trial investigating the safety and tolerability of a novel synthetic DNA-encoded monoclonal antibody (DMAb) therapeutic technology for the prevention of Zika virus infection.

DMAb therapeutic technology is unlike all known conventional therapeutic antibodies in that DMAbs are made inside of people, not manufacturing plants. Patients are administered DNA instructions to equip their bodies with the necessary tools to make their own highly specific antibodies against pathogenic targets such as bacteria, virus-infected cells and cancer cells.

David B. Weiner, Ph.D., executive vice president, director of the Vaccine Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, has been leading the research and development of the DMAb technology.

“DMAb technology is changing the clinical story as we know it. In just the last few years we’ve conducted detailed preclinical studies developing this new platform and have demonstrated in vivo production of DMAbs using the CELLECTRA® delivery system,” said Weiner. “This approach represents the potential for major advancement over traditional monoclonal antibody approaches and may broaden therapeutic strategies opening new patient markets to the benefits of antibody-based therapies for disease prevention or treatment.”

In 2016, The Bill & Melinda Gates Foundation awarded funding to The Wistar Institute to move DMAb technology from prototype into a clinical candidate for eradicating an emerging infectious disease.

Within two short years, a phase 1 clinical trial for Zika DMAbs is now enrolling participants. The trial will be led by Pablo Tebas, M.D., professor of infectious diseases at the Perelman School of Medicine at the University of Pennsylvania. It is a single center, open-label, dose escalation trial that will enroll up to 24 healthy volunteers who will receive up to four doses of Inovio vaccine/product INO-A002.

“This is a completely novel technology that could change the way we deliver antibodies as therapeutic agents and may have the potential to be fast-tracked into clinical trials. While there are still questions to be answered, this could be useful not only for Zika, but for other emerging infections as well,” said Tebas.

“While this trial targets Zika virus infection, we will gain important data from this study towards development of a broad range of our DMAb programs targeting infectious diseases, cancer, inflammation, as well as cardiovascular disease,” said J. Joseph Kim, Ph.D., president and CEO, Inovio Pharmaceuticals, Inc. “Our collective goal is to develop this new and unique approach to monoclonal antibody technology that would allow for a new pipeline of high-impact DMAb products, which can be developed with corporate partnerships, external funding and collaborations.”

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.