A Better Way Series, Part V: Microvesicles Allow Repeat Dosing
Jonathan Thon, Ph.D. • March 14, 2023
In this blog series, we’ve covered why microvesicles are safer and have more specific, tunable cell tropism than viral vectors and synthetic particles. In our final installment of the series we’ll discuss another important property: dose repeatability.
In an ideal world, a disease can be cured with a single dose. Unfortunately this is not always possible. In some cases, a certain threshold percentage of stem and progenitor cells will need to be edited before a sustainable clinical benefit is seen, which may require more than one dose. In other cases, the stem and progenitor cells won’t be targetable at all and it will be necessary to treat, rather than cure, the disease using regular doses that edit each new generation of shorter-lived non-stem cell. Gene therapy delivery vehicles therefore need to be compatible with repeated doses into the same patient.
In Part IV of this series we highlighted patients’ immune responses to viral vectors and synthetic particles can pose an important safety risk. The same immune responses are also an obstacle to dose repeatability. If a gene therapy delivery vector does not possess a property called immune privilege, the patient’s immune system may recognize it as an external threat and begin priming the system to attack the next similar vector it encounters. An immunogenic gene therapy delivery vector will thus act essentially as a vaccine against future doses of the same therapy.
Lack of immune privilege is a particular problem for viral vectors, given their pathogenic origin: viruses are public enemy number one for the human immune system. Synthetic particles can also trigger immune or allergic responses in a small percentage of the population, although they have better immune privilege than viral vectors for most individuals, permitting a limited number of repeat doses10.
Microvesicles, on the other hand, are derived directly from human cells and are recognized by the immune system as “one of our own”. STRM.BIO EVs are particularly amenable to repeat dosing–which is transformative. Our preclinical studies have shown no meaningful change in blood cell counts, no platelet elevation, no impact on coagulation parameters, no liver or kidney toxicity. Bloodwork has remained normal, as has cytokine expression. We’ve seen no evidence of inflammation or perturbed hematopoiesis, and no evidence of toxicity. This is an exceptional start that offers the prospect of the best dose repeatability available in the gene therapy delivery ecosystem today; and the opportunity to open up the landscape of diseases that can be treated.
10Kenjo, E. et al. Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice. Nat Commun 12, 7101, doi:10.1038/s41467-021-26714-w (2021).
The gene therapy ecosystem is undoubtedly on the cusp of a transformative breakthrough. Although microvesicles are at a relatively early stage of development, there is already strong evidence that they have many advantages over other technologies. That’s why we at STRM.BIO believe that microvesicles can deliver more than just gene therapies: we believe that they will also deliver the final breakthrough that will democratize the field of gene therapy and bring lifesaving treatments and cures for multiple diseases to life.