Chemistry of Life Processes Institute has selected two high-risk, potentially high-reward biomedical research projects to receive CLP Cornew Innovation Awards.  The 2021-22 awards will support the development of new technology for creation of viral nanoparticles for gene therapy and research to identify proteins distinguishing ALS pathology in the brain.  Each interdisciplinary team of CLP investigators will receive $50,000 for one year to help launch their transdisciplinary, blue-sky projects.

A Platform Enabling Self-Assembling Synthetic Viral Nanoparticles for Gene Delivery

Danielle Tullman-Ercek, Professor of Chemical and Biological Engineering and Joshua Leonard, Associate Professor of Chemical and Biological Engineering, are working together to build a technology platform that will enable a new generation of gene delivery technologies that can be used for a broad range of clinical applications.

The project merges the collaborators’ existing knowledge around using engineered virus shells as gene delivery vehicles.  The researchers hope to mitigate current challenges with such vehicles that have limited the technology’s success, such as not going where they were intended to, or the risk of immune rejection.

“These challenges line up pretty nicely with a new, emerging scientific area studied by my lab,” said Leonard. “We have fairly recently come to understand a process in which cells send ‘bubbles’ containing various biological molecules to other cells somewhere else in the body, causing those recipient cells to carry out new functions. My group has been working to figure out how to tap into this process to overcome some of the challenges with using virus shells as gene delivery vehicles.”

Determining the changes necessary to make the virus shells compatible with the cell messenger bubbles taps into Tullman-Ercek’s expertise.

“I’ve spent the past decade engineering the virus-like particles and figuring out ways to do that at really high throughput—looking at thousands of different changes we can make and how each one of them might behave in a given context and finding the one that’s best,” says Tullman-Ercek. “We hope to be able to prove the most feasible method in under a year.”

The call for proposals provided the impetus to do something “potentially disruptive” and learn from the industry experts on CLP’s Executive Advisory Board who provided the seed money for the awards, said the researchers.

“The whole thing kicks off with what is essentially free consulting provided by CLP’s board members,” said Leonard. “During our presentation to the board, we received great feedback. This interaction is a really smart part of the design of this award mechanism.”

The Proteoform Landscape of TDP-43 Pathology in ALS Brain

Neil L Kelleher, Walter and Mary E. Glass Professor of Molecular Biosciences and director of CLP and Northwestern Proteomics, P. Hande Ozdinler, Associate Professor of Neurology and Steven Patrie, Research Associate Professor of Chemistry and Director of Neuro Proteomics within the Proteomics Center of Excellence, received the Cornew award to reveal the proteoform landscape of TDP-43 pathology in the ALS brain.

“Accumulation of TDP 43, a sticky protein that binds to many other proteins forming aggregates, is present in about 95% of all ALS patient brains,” said Ozdinler.  “It is considered one of the most common causes of pathology in ALS.”

Understanding why TDP 43 protein causes aggregations and how they interact with other proteins are the aims of the collaboration. Insights gained from the project can pave the way for therapeutic interventions that can stop them from forming.

“Our collaboration with Steve and Neil is very important because their technological expertise can reveal how many different forms of TDP there are, what other domains are present, and which are missing,” said Ozdinler.

Kelleher and Patrie are experts in top-down proteomics, an advanced analysis method that relies on mass spectrometry to examine intact proteoforms with complete molecular specificity.

“There are very few laboratories around the world that are dedicated to pushing the top-down field in ways that help solve biological problems,” said Patrie. “With bioinformatics and biostatistics, we can help identify TDP pathologies and understand the structural elements that are defined by the molecular heterogeneity associated with post-translational modifications.  The top-down technology workflow is well geared towards managing the molecular heterogeneity associated with proteins.”

Cornew awards granted over the past 12 years have yielded a 24-fold return in new federal funding for Northwestern research programs. The awards were named for the Board’s founding chair, Stuart Cornew.  The Board’s current chair is Dr. Andrew (Andy) Chan who was the recipient of the 2021 Northwestern Alumni Award.

“These kinds of mechanisms are super useful for more high risk, high reward projects,” said Leonard. “Incentivizing new and ambitious projects pushes people who want to work together over the hump to make it happen.”

by Lisa La Vallee