Trends

The rise of CRISPR-mediated genome editing provides a powerful tool for use in genetic-engineering applications. Although recent studies using human embryos demonstrated off-target effects, CRISPR may eventually demonstrate utility in gene therapy applications.

Within complicated human systems, there is greater potential for adverse effects that may not be observed in preclinical studies. An example of this is the occurrence of leukemia in patients receiving treatment for X-linked severe combined immune deficiency (SCID) using adeno-associated viral vectors (AAVs).

Clinical translation is often impaired by limitations associated with the in vitro experiments conducted to validate the vector formulations. These assays often assess only one aspect of gene delivery in a nontherapeutic context. For instance, many clinical trials have demonstrated limited efficacy due to the loss of transgene expression over time.

Another impediment is the tendency for in vitro experiments to poorly represent physiological conditions. Vector circulation and clearance, as well as nuclear translocation of the genetic cargo, are critical aspects of gene delivery that are not adequately addressed using conventional experimental design. For instance, immune responses to treated cells impaired the efficacy of gene therapy approaches for treating hemophilia B and lipoprotein lipase deficiency.