STRM.blog

At STRM.BIO we have selected microvesicles as the most promising delivery technology for our gene therapies. In the previous installment of this series, we outlined the superior cell targeting and biodistribution of microvesicles compared to viral vectors and synthetic nanoparticles. In today’s article we’ll review how these technologies compare on the safety front.

Gene therapy safety relates not just to the side effects experienced by patients but also to product consistency. Regulators set stringent chemistry, manufacturing, and controls (CMC) requirements as part of the drug evaluation and approval process; the intent is to ensure that manufacturers can deliver a consistent and predictable product. 

Viral vectors are based on human pathogens and present a number of safety concerns related to this origin. For example, some viruses—and some viral gene therapy vectors—can insert their DNA into the cell’s genome in a way that can potentially cause cancer and other unintended effects.¹ ² ³ Other viral vectors undergo unanticipated and unpredictable molecular changes during the manufacturing process that can create an inconsistent product.^{4 5} Further, the human immune system has evolved a range of defenses against viruses, and unpredictable immune responses to viral gene therapy vectors can cause side-effects ranging from mild flu-like symptoms to life-threatening immune system storms. Overcoming these safety concerns is a major focus for the research and development teams that are continuing to develop viral vectors for gene therapy.

Synthetic particles were explicitly designed as a safer version of viral vectors and for the most part they live up to this promise, albeit with trade-offs in terms of delivery efficiency. Synthetic particles do not interact directly with the cell’s DNA, and they are much easier than viral vectors to manufacture consistently and at scale. However, although the current generation of synthetic particles has a better safety profile than viral vectors, a small percentage of the population may still mount an immune, inflammatory, or (very rarely) even an allergic response to the ingredients of some formulations.⁶ 

Microvesicles are a relative newcomer to the gene therapy delivery technology landscape; their ability to deliver DNA and other molecules between cells was first reported in 2001.⁷ However, as microvesicles are naturally secreted from multiple types of cells, they are present in blood and other biological products and have therefore been part of every human blood transfusion and organ transplantation ever performed, going back more than two centuries. This long history of transfusion of microvesicles into human recipients demonstrates their safety. They can also be readily manufactured at scale from liquid cell culture, and are amenable to repeat dosing – greatly expanding the breadth of diseases and gene therapies they can be applied to.

In the final installment of this series of articles, we’ll discuss how these advantages affect dosing in patients.  

¹Rothe, M., Modlich, U. & Schambach, A. Biosafety challenges for use of lentiviral vectors in gene therapy. Curr Gene Ther 13, 453-468, doi:10.2174/15665232113136660006 (2013).
²Check, E. Regulators split on gene therapy as patients show signs of cancer. Nature 419, 545-546, doi:10.1038/419545a (2002).
³Goswami, R. et al. Gene Therapy Leaves a Vicious Cycle. Front Oncol 9, 297, doi:10.3389/fonc.2019.00297 (2019).
⁴McCarron, A., Donnelley, M., McIntyre, C. & Parsons, D. Challenges of up-scaling lentivirus production and processing. J Biotechnol 240, 23-30, doi:10.1016/j.jbiotec.2016.10.016 (2016).
⁵Giles, A. R. et al. Deamidation of Amino Acids on the Surface of Adeno-Associated Virus Capsids Leads to Charge Heterogeneity and Altered Vector Function. Mol Ther 26, 2848-2862, doi:10.1016/j.ymthe.2018.09.013 (2018).
⁶Mohamed, M. et al. PEGylated liposomes: immunological responses. Sci Technol Adv Mater 20, 710-724, doi:10.1080/14686996.2019.1627174 (2019)
⁷Ratajczak, M.Z., Ratajczak, J. Extracellular microvesicles/exosomes: discovery, disbelief, acceptance, and the future?. Leukemia 34, 3126–3135 (2020). https://doi.org/10.1038/s41375-020-01041-z