Gene therapy delivery system successfully targets CD90+ hematopoietic stem cells in vivo

Researchers in the lab of Hans-Peter Kiem, MD, PhD, at Fred Hutch Cancer Center have devised a method that could one day treat genetic hematologic disorders by correcting how the body makes blood cells. Their abstract, “Targeted Multiplexed Virus-Like Particles (MVPs) Enable Robust In Vivo Hematopoietic Stem Cell (HSC) Engineering,” is one of several the team presented at the annual meeting of the American Society of Gene and Cell Therapy (ASGCT) in New Orleans, May 13-17. 

Kiem, a world-renowned researcher in gene therapy and stem-cell engineering, recently sat down with Hutch News to explain the significance of the targeted MVP study and to highlight some of the other work presented by members of his lab at the ASGCT meeting. Kiem is deputy director of the Translational Science and Therapeutics Division and holds the Stephanus Family Endowed Chair for Cell and Gene Therapy.

Read on for his insights on the potential of gene therapy in treating conditions from sickle cell disease to Alzheimer’s.

Why are Fred Hutch scientists studying HSC gene therapy?

Gene therapy is a way to treat conditions by introducing a gene into a person’s cells or editing a defective gene they already have. For example, people with thalassemia or sickle cell disease have a genetic defect that affects red blood cells. By using gene therapy to modify their HSCs — which give rise to all other blood cells — we can correct how their red blood cells are made. HSC gene therapy can be used for conditions caused by defects in other blood cells as well, such as T cells, B cells and granulocytes.

What’s interesting about CD90+ HSCs specifically?

CD90+ HSCs are of particular interest because our previous research has shown this subset of HSCs plays a major role in both short-term and long-term repopulation of blood cells after myeloablative conditioning (high-intensity chemotherapy and/or radiation) and blood or marrow transplantation. This means that by modifying a person’s CD90+ HSCs, we have a good chance of generating enough healthy blood cells to have a positive therapeutic effect. In thalassemia and sickle cell disease, for instance, we need to reach a threshold of about 20% to 30%.

What’s driving the quest for in vivo gene therapy rather than ex vivo?

All gene therapy approaches currently used in the clinic for genetic diseases are ex vivo, meaning we have to take the patient’s cells out of their body to modify them. This requires a sophisticated infrastructure. We have to collect the patient’s HSCs, bring them to a specialized facility, modify them and cryopreserve them. Then the patient has to undergo conditioning to suppress or ablate their blood cell–forming system, which requires hospitalization and can cause complications. Then we have to infuse the modified cells into the patient and wait for the cells to engraft. The process can take three to six months and many weeks of inpatient hospital care.

How would in vivo therapy be different?

An in vivo approach would change everything. We would give the therapy through a syringe or very short infusion into the patient’s bloodstream in a single clinic visit, and it would work on their HSCs inside their body. This way, gene therapy could be made available to many more people — not only in the United States but in low- and middle-income settings around the world, like sub-Saharan Africa, where millions are living with thalassemia and sickle cell disease.

What novel approach did you share at ASGCT for altering HSCs in vivo?

When might this approach move from the lab to patients?

We have to confirm our data in additional studies in different animal models, and then we’ll hopefully move it into clinical trials with patients. A similar in vivo approach is already being used in CAR T-cell studies, in which patients with cancer receive an injection of particles that target their T cells. I don’t think it will be that far off before we can do this in vivo for patients with genetic diseases too.

Your group presented another abstract related to both CD90 and CAR T-cell therapy for acute myeloid leukemia (AML). What was new about this project? 

AML has been very hard to treat with CAR T cells, so we’re looking for solutions. CD90 is not only on normal HSCs but also on cancer stem cells — in particular, on AML— so we decided to try targeting CD90+ leukemia cells. The challenge was getting the CAR T cells to act against the leukemia without eliminating the normal HSCs. We showed we can modify normal HSCs, knocking out CD90 on them, and they still function normally. This is new. It means we can ablate CD90 on normal HSCs to protect them, transplant those into the patient and then come in with an anti-CD90 CAR construct to kill the leukemia. 

This project on targeted leukemia stem cell immunotherapy was also presented by Justin and involved graduate student Nick Petty and senior staff scientist Stefan Radtke, PhD. They’ve been spearheading the work.

Along with blood disorders and cancer, your lab is working to improve treatment for leukodystrophies. What’s exciting in that realm?

Neurotropic lysosomal storage diseases, like metachromatic leukodystrophy or adrenoleukodystrophy, can damage the central nervous system (CNS). It’s been known for some time that white blood cells called monocytes can migrate to the CNS and function as glial cells, mitigating the damage. We call them microglial-like cells. This allows us to treat leukodystrophies with allogeneic transplantation. The idea is that normal microglial-like cells derived from the stem cells of a donor replace a patient’s abnormal microglial cells. However, a limiting factor is the trafficking of these cells to the CNS. We’ve studied how to improve it. Nick presented our abstract on facilitating engraftment of the cells with CSF1R inhibitor treatment. 

Improving trafficking and replacement could impact not only leukodystrophies but hopefully also neurodegenerative conditions, like Alzheimer’s disease. In mouse studies, it has already been shown that the replacement of abnormal microglia with normal microglia can cure Alzheimer’s. This is why this work is so important.

This work was supported by grants from the National Institutes of Health; amfAR, The Foundation for AIDS Research; and the Fred Hutch Immunotherapy Integrated Research Center Catalyst Award.