RNA editing has the potential to alleviate pain and treat diseases. Directed RNA editing is challenging because it needs to deliver a specific edit to potentially hundreds of RNA molecules in the cell. Joshua Rosenthal’s RNA editing system, while not precise, creates thousands of protein mutations throughout the cell. Rosenthal and Jeffrey Hubbell are collaborating to use RNA editing in cancer immunotherapy, increasing the number of neoantigens in cancer cells to increase the mutational burden and make tumors more sensitive to immunotherapy. Tumors with more neoantigens are more responsive to immunotherapy, making this approach promising. The hope is that this approach will not only make cold tumors easier to detect by the immune system but also more responsive to immune checkpoint inhibitors. The collaboration between Hubbell and Rosenthal shows the value of interdisciplinary research and the potential for unexpected breakthroughs.
Unexpected collaboration aims to improve cancer immunotherapies
Bioengineer Jeffrey Hubbell and neurobiologist Joshua Rosenthal are collaborating to improve the efficiency of cancer immunotherapies through directed RNA editing. While their research interests initially seemed dissimilar, a casual conversation in 2018 at the Marine Biological Laboratory (MBL) sparked their collaboration. Today, they are exploring the potential for clinical translation and have filed for a patent on their approach. Rosenthal’s lab had previously developed directed RNA editing systems, but a failed experiment inspired the idea to apply RNA editing to immunotherapies.
Harnessing the immune system against cancer
The immune system is one of the most promising tools to fight cancer. Immune checkpoint inhibitors (ICIs) are therapeutics that “release the brakes” on the immune system to attack cancer cells, and they have revolutionized the treatment of certain types of tumors.
Rosenthal and Hubbell are working to improve the efficiency of ICIs using directed RNA editing, which could lead to more effective cancer treatments. The potential of their approach has led to discussion of starting a biotech company if it continues to show promise.
The collaboration between Hubbell and Rosenthal highlights the value of interdisciplinary research and the potential for unexpected breakthroughs.
Using RNA Editing to Improve Cancer Immunotherapy
Immunotherapy has shown great promise as a tool to fight cancer, but there is room for improvement. Normal cells and cancer cells express very similar proteins, making it difficult for the immune system to distinguish between them. However, cancer cells contain mutated proteins called neoantigens, which differentiate them from normal cells. Tumors with a higher mutational burden, meaning they have more neoantigens, are more responsive to immunotherapy. However, some cancers have low mutational burdens, making them resistant to treatment.
Jeffrey Hubbell and Joshua Rosenthal are collaborating to increase the number of neoantigens in cancer cells using RNA editing technologies developed by Rosenthal’s lab. They hope this will increase the mutational burden, making tumors more sensitive to immunotherapy. They also expect the approach to trigger epitope spreading of immunity, causing immune cells to attack even distant tumor cells.
Preliminary results from a mouse model for an aggressive melanoma are encouraging, with tumors treated with RNA editing shrinking substantially. The next step is to test the approach in a melanoma model engineered to develop human-like tumors, as well as in a mouse model for breast cancer.
The sheer number of changes made to cancer cells by RNA editing activates immune cells and stunts tumor growth, according to Lisa Volpatti, a postdoctoral fellow in Hubbell’s lab who has been performing cancer studies in mice and characterizing the immune environment of the tumor. The hope is that introducing abundant neoantigens via RNA editing will not only make cold tumors easier to detect by the immune system but also more responsive to immune checkpoint inhibitors, which have low efficacy in some cancers, such as breast and brain cancers.
Interdisciplinary Collaboration in Science
The collaboration between Hubbell and Rosenthal is an example of the value of interdisciplinary research and the potential for unexpected breakthroughs. Rosenthal’s “failed” RNA editing experiment, which accidentally made thousands of protein mutations in a cell, turned out to be a new approach to improving cancer immunotherapies.
Hubbell, who has founded three companies based on his research and holds 77 patents, emphasizes the importance of testing the approach in multiple mouse models to translate the data from academic research to clinical development.
The use of RNA editing to increase the mutational burden of tumors is a promising avenue for improving cancer immunotherapy. The approach may also broaden the use of immune checkpoint inhibitors, making them more effective in cancers that are currently resistant to treatment.
RNA Editing’s Potential for Medical Use
RNA editing is a natural process that modifies the types of proteins produced in cells. Directed RNA editing has the potential for therapeutic use to alleviate pain or treat diseases. One project by Josh Rosenthal aims to modify the proteins that transmit pain signals, dampening their excitability as an alternative to blocking them with addictive opioid drugs.
Directed RNA editing is challenging because it needs to deliver a specific edit to potentially hundreds of RNA molecules in the cell. Rosenthal hit upon an RNA editing system that was impressively active, creating thousands of protein mutations throughout the cell. While such off-target edits are usually undesirable, they may have value in cancer immunotherapy.
Using RNA Editing for Cancer Immunotherapy
Jeffrey Hubbell and Joshua Rosenthal are collaborating to increase the number of neoantigens in cancer cells using RNA editing. The goal is to increase the mutational burden, making tumors more sensitive to immunotherapy. Tumors with more neoantigens are more responsive to immunotherapy, making this approach promising.
Hubbell had done preliminary work introducing one neoantigen into a tumor using an adenovirus, but the approach was only partially effective. Rosenthal’s RNA editing system, while not precise, may create thousands of neoantigens. The hope is that this approach will not only make cold tumors easier to detect by the immune system but also more responsive to immune checkpoint inhibitors.
Potential for RNA Editing in Medicine
RNA editing has the potential for therapeutic use beyond cancer immunotherapy. Rosenthal’s project to modify proteins that transmit pain signals is one example. Precise directed RNA editing is necessary for therapeutic use, and Rosenthal emphasizes the importance of minimizing off-target edits while ensuring that the system is active enough to edit a high percentage of RNA molecules in the cell.
The potential for directed RNA editing to address medical needs makes it an exciting area of research. The challenge lies in developing a system that can deliver specific edits to RNA molecules in cells. The collaboration between Hubbell and Rosenthal shows the value of interdisciplinary research and the potential for unexpected breakthroughs.
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