Applying siRNA Therapy Beyond the Liver

Judy Lieberman, MD, PhD

The first therapeutic based on small interfering RNAs (siRNA) was approved by the FDA in 2018. Since the, 4 additional siRNA-based therapies have been approved. Although all 5 of these target the cells of the liver, as these cells make a relatively easy target for the siRNA modality.

Judy Lieberman, MD, PhD, the endowed chair in cellular and molecular medicine at Boston Children’s Hospital, however, seeks to expand the use of siRNA to therapeutic applications beyond the liver, such as cancer and immune diseases. At the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024, she presented about the research she has done on potential methods of applying siRNA to various indications. CGTLive® spoke with Lieberman after her presentation to learn more about her innovation in this field.

CGTLive: Can you give some background information about your presentation on siRNA at Tandem 2024?

Judy Lieberman, MD, PhD: I gave a talk in a session about gene therapy and cell therapy that looked at the broader advances being made, not specifically in transplantation, but that might be applicable in the future to transplantation. My area of expertise is in RNA interference therapy, in which small double-stranded RNAs get into a cell and can specifically knock down the expression of 1 gene at a time. I was involved in that field from the beginning. I was the first person who showed you could use small interfering RNAs (siRNAs) in an animal model to treat disease and also to develop targeted RNA therapy where you could design RNAs that got into a specific cell type, like a T-cell or a cancer cell, and knock down 1 specific gene for therapy.

What were the key points you covered during your talk?

In 2018, the first siRNA-based drug was approved to treat a genetic form of amyloidosis. Now there are 5 siRNA drugs that are approved, mostly to treat genetic diseases that are rare, but more recently they also include a treatment for hypercholesterolemia that knocks down a gene called PCSK9 that's involved in the uptake of cholesterol. But all of those targets are targets that are expressed in the liver, where it's very easy to deliver siRNAs and get gene knockdown. So far, there aren't any clinically approved siRNA based drugs that target outside the liver. Also, there's not a lot of drug development to try to expand to the kinds of targets outside the liver.

I'm an immunologist and I'm also a hematologist by training. I've always been interested in whether we could harness this endogenous pathway of gene knockdown to treat cancer and immune diseases. I first developed a way that you could use antibody fragments that are fused to protamine, which is the protein in sperm that binds to DNA and puts it in a very small package in sperm. I found that I could use these fusion proteins to bind to RNA and deliver siRNAs and get gene knockdown in any cell very specifically: in all lymphocytes or only in activated lymphocytes, [etc.], which is something that could be applied for transplantation to deal with, say, graft versus host disease. But it's never been tried. That works, but it's a little challenging to manufacture and develop that as a drug.

Then I started working with conjugates of aptamers, which are like nucleic acid antibodies that can bind with very high affinity, like an antibody, to a specific cell surface receptor... I was interested in HIV and preventing sexual transmission for HIV so I figured a way of using this CD4 aptamer, since all the cells that become infected with HIV are CD4-positive, to actually prevent sexual transmission of HIV in humanized mouse models.

But more recently, I've been focusing on using aptamers that target solid cancers to deliver siRNAs that could either kill the tumor directly or help induce an immune response to broaden the range of tumors that could be targeted by immunotherapy. We knock down genes that would increase the tumor antigens by blocking, say, DNA repair or RNA quality control pathways that would increase the phagocytosis of tumor cells by dendritic cells by knocking down a “Don't eat me” signal that prevents the dendritic cell from taking up the tumor cell, and things like that. And they work! But so far, I haven't commercialized them at all.

That was what my talk was about, that there are these ways to use RNA interference. Nowadays with chemical modifications, you can treat people with a single injection of an siRNA subcutaneously and it lasts for a year. I mean, one of the drugs is given every 3 to 6 months, but the even newer chemistries last really for a long time, so that's attractive. I think this technology could be used in the transplant setting.

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.