We met WCMM clinical researcher Anders Wittrup for a chat about his background, ongoing projects and future plans.
The Challenge of RNA Delivery
Anders explained that one of the main hurdles in RNA therapeutics is ensuring the RNA escapes the endosome once it enters the cell. Without this escape, RNA cannot exert its therapeutic effect. He pointed out that inefficient endosomal escape is a common issue for nucleic acid-based drugs like DNA and RNA.
It's relatively easy to get things into endosomes, but it's very tricky to get them out. That's the step we want to improve." Anders and his team are particularly interested in developing methods to detect, visualize, and measure the efficiency of RNA delivery into cells.
Advances in RNA Delivery Technologies
During our conversation, Anders touched on different strategies for administering nucleic acids, including lipid nanoparticles (similar to those used in COVID-19 vaccines). These nanoparticles, often administered intravenously, primarily target the liver. However, by attaching ligands recognized by specific tissue receptors, delivery can be targeted more precisely.
Another challenge is RNA stability, as unmodified RNA degrades quickly in the bloodstream.
You can modify RNA to make it more stable and less susceptible to breakdown by RNAses, but unmodified RNA has a half-life of just seconds or minutes."
Anders provided examples of RNA therapeutics, such as using small interfering RNAs (siRNAs) to treat genetic disorders like amyloidosis by silencing aberrant protein production. Additionally, RNA is being explored as a method for delivering CRISPR-Cas9 and prime editors, allowing for the rewriting of genetic material. However, while the liver is easily targetable, other tissues—such as tumors—present challenges due to poor circulation and tight endothelial barriers.
Targeting Tumors and Other Tissues
Targeting RNA therapeutics to tumors is particularly difficult. Anders emphasized that delivering RNA to the vast majority of tumor cells requires formulations that can penetrate dense tumor tissues. However, this challenge is not limited to tumors, as many tissues possess tight endothelial barriers.
One method his lab is investigating involves conjugating RNA to cholesterol to target rapidly dividing tumor cells. "With cholesterol, it's very difficult for cells to escape because it's a building block for dividing cells," Anders noted.
Visualizing RNA Delivery
Rather than focusing on developing treatments directly, Anders' lab is committed to refining delivery methods by visualizing the process at a microscopic level. His team is developing platforms that could be used to improve the delivery of various RNA-based therapeutics.
One key collaboration is with AstraZeneca, where Anders has been instrumental in creating techniques to monitor delivery efficiency. During his postdoc at Harvard Medical School, Anders discovered that cells have endogenous sensors for detecting endosomal damage—an indicator of successful delivery.
Building a World-Leading Lab
Anders has assembled a world-class team at Lund, including three PhD students, two postdocs, and a part-time technician.
When I was starting the lab, I thought we would be overshadowed by bigger groups, but it's not easy for others to jump into this field. You need solid microscopy experience and the right hardware, which we now have.
His lab focuses on translational science, with their tools being utilized by both pharmaceutical companies and academic institutions. However, Anders notes they have resisted becoming a service provider, preferring to focus on research that drives the field forward.
Collaborations and Future Directions
Being part of WCMM has been crucial for Anders' work. The funding allowed him to recruit staff and set up his lab, while the collaborative network has been invaluable for generating ideas and learning how to organize his research more effectively.
"Especially with Vinay (Swaminathan), we've been sharing microscopy techniques."
Clinically, Anders specializes in brain tumors, with an initial focus on improving RNA delivery for treating glioblastoma, a highly malignant brain tumor. The closed environment within the skull offers a unique opportunity for localized delivery, which could be combined with targeting dividing cells. However, Anders acknowledges that we're still in the early stages of developing these treatments.
Looking Ahead: Future Avenues for Research
Looking ahead, Anders’ lab is pursuing two main avenues: developing more advanced strategies for nucleic acid delivery and going deeper into understanding what happens after the molecule is delivered.
I want to track individual molecules, see their orientation, and analyze them with higher resolution. So far, unexpected things have turned up, and I think more will continue to do so."
Investing in Cutting-Edge Equipment
In May 2022, Anders received an equipment grant from the Fru Berta Kamprad Foundation, which allowed him to acquire a high-speed instant structured illumination microscope (iSIM). This state-of-the-art system enables 3D time-lapse imaging at super-resolution, ideal for analyzing dynamic processes in cells.
"The system balances spatial and temporal resolution perfectly, allowing us to capture processes in real-time," said Anders.
Conclusion
At the end of this Fireside Chat, we extend our gratitude to Anders Wittrup for sharing his valuable insights into the rapidly evolving field of RNA therapeutics. His dedication to advancing RNA methodologies—particularly in overcoming delivery challenges—continues to push the boundaries of what is possible. We wish Anders and his team continued success as they bring the field to new heights!
