A Better Way Series, Part III: Microvesicles Have Specific and Tunable Cell Tropism
Jonathan Thon, Ph.D. • February 27, 2023
In Parts I and II of this series we reviewed why a breakthrough in gene therapy delivery technology is so critical to the future of the field, and introduced STRM.BIO’s microvesicles as a better way to deliver DNA editing technology into the right cells through a simple injection. In this article we’ll outline the unique advantages of microvesicles over other delivery technologies in three key areas, beginning with cell tropism: the targeting of the therapy to the right cells in the body.
The human body contains hundreds of different kinds of cells, and each type has a unique combination of proteins and other molecules embedded in its outer membrane. Cells recognize each other in the body via complex interactions between these surface molecules—like a secret handshake. Gene therapy delivery vectors are designed to mimic this ability to recognize a specific cell type.
As an example, to treat inherited blood disorders, you need a gene therapy delivery vector that can enter bone marrow cells; to cure it, the vector needs to target the long-lived stem and progenitor cells that will continue to produce new generations of bone marrow cells throughout the patient’s lifetime. It’s also important that gene therapy vectors deliver the editing cargo only into the relevant target cells; off-target cargo delivery increases the dose required to edit the DNA of the target cells, and also risks causing side effects.
The outer shells of viruses have evolved to interact with and enter human cells, and viral vectors for gene therapies exploit this property to deliver their cargo. However, the natural cell tropism of viruses is not well suited for many gene therapy applications. For example, vectors based on retroviruses and lentiviruses can only infect dividing cells, while adenovirus vectors can be taken up by any cell type, increasing both the risk of side-effects and the required dose.
Synthetic particles, on the other hand, have no innate cell tropism, although many types accumulate in the liver as part of the body’s process for eliminating foreign materials. Some specific cell tropisms can be engineered onto this blank slate by incorporating cell surface proteins during the manufacturing process, or through chemical modification of the synthetic lipid or other polymer that makes up the particle. However, these relatively crude modifications cannot replicate the much more complex combinations of cell surface molecules found on human cells, and the resulting cell tropism is often too broad and sometimes unpredictable in vivo. Modifying the particles can also cause side-effects and increase manufacturing costs.
The specific cell tropism of microvesicles is one of the main reasons the STRM.BIO team is so excited to be working on this technology. Microvesicles inherit the complex combination of surface proteins expressed by their parent cell when they bud from its membrane. This means that microvesicles derived from different cell types have different cell tropisms, making them a highly tunable option for diverse gene therapy applications. Some microvesicles have an innate ability to home to hematopoietic stem cells in the bone marrow and other locations, offering the prospect of long-lasting in vivo treatments and even cures for inherited hematopoietic disorders¹. Cell tropism can be further tuned relatively easily by genetically engineering the microvesicle source cells to knock out or modify any undesirable cell surface proteins. To date, we have shown that our microvesicles can be loaded with pDNA, RNA or RNP (eg. CRISPR/Cas 9 gene editors) and that they will deliver these cargo into cells; if pDNA, we have shown that these cargos are translocated to the nucleus and transcribed into mRNA, and functional protein is successfully produced from both pDNA and mRNA cargos. In our animal studies to date we have shown that our cargo-loaded microvesicles target long-term hematopoietic stem cells and hematopoietic stem and progenitor cells following intravenous injection, and that this cargo is delivered and expressed in vivo.
Microvesicles have other advantages, too, and in the next article in this series we’ll explore their benefits related to patient safety.