RNA-Based Therapy Still Holds Many Future Opportunities

Judy Lieberman, MD, PhD

Judy Lieberman, MD, PhD, the endowed chair in cellular and molecular medicine at Boston Children’s Hospital, gave a talk on the topic of small interfering RNA (siRNA) research at the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024. After her presentation, CGTLive® spoke with Lieberman to learn more about RNA therapeutics.

Lieberman discussed the history of RNA therapy so far, noting how far things have already come in the past 20 years. Afterwards, she discussed future opportunities for siRNA therapy, such as targeting cells outside the liver and addressing indications as wide ranging as diabetes, hypertension, and infection even with siRNA therapy targeted at liver cells.

CGTLive: How would you summarize the big picture implications of your presentation on siRNA?

Judy Lieberman, MD, PhD: I think that we're in a new world. Like there were the talks in this session about personalized cancer vaccines that use mRNA as the vaccine, or CAR T-cells that can be modified by mRNAs, gene knockdown, or editing. There are so many opportunities for improving therapy using these new techniques. I mean, just recently, CRISPR/Cas9 editing was approved for treating sickle cell anemia and thalassemia. It's sort of like the future is now. When CRISPR/Cas9 was first shown to work it seemed like such a long roadway to go from what we did to be able to use it safely in patients. But people have just basically solved the problems. It takes a long time. Like for RNA therapeutics, it took 20 years from the demonstration that this phenomenon worked—first in worms and then in humans—to be able to use it and control it well enough and safely enough to use it as a drug. siRNA therapies built on the experience that people had developing antisense oligonucleotide drugs. The mRNA vaccines have built on what people learned from developing siRNA drugs. And the same is true for CRISPR because a lot of these gene manipulating therapies have a similar problem: How do you get nucleic acids into the cell? It isn’t so easy because the nucleic acids are ionic; they don't go through membranes. Even when they get into cells, they go into endosomes and getting them out of the endosome is a challenging problem. But all of these technologies are incredibly powerful. They have similar problems to deal with and they're making it. If you look at the PDR handbook, it's amazing for someone like me who graduated from medical school in 1981. The PDR now it's like mostly not conventional small molecules anymore. There’s antibodies, there's new kinds of therapies, and I think they’re going to improve our treatment.

Can you discuss some area of interest for further research in this field?

I think for RNA interference, which is what I know the most about, it’s going beyond the liver. Both academic investigators and Alnylam Pharmaceuticals, which is the leading drug company in this arena, have developed ways to get into the brain and the eye by putting a lipid tail on the RNAs. I think that's an amazing opportunity now. I believe cell-targeted RNA can be delivered to any cell. So I think that's an opportunity for treating a lot of different diseases. Then even in the liver, most of the early drug development was in these rare genetic diseases, but the liver is like the factory of the body that makes a lot of proteins. There are all kinds of opportunities in clinical development for things like hypertension, diabetes, and fatty liver. I think for infection there's a lot of opportunities, too because in lower organisms, RNA interference is actually one of the immune defenses against infection.

This transcript has been edited for clarity.

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REFERENCES
1. Lieberman J. The silent treatment: siRNA therapeutics. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas.