Vector Engineering Helps to Usher in the Next Generation of Viral Vector Based Gene Therapy

Particular viruses have been identified as gene delivery vehicles to carry specific genetic materials into certain cells or tissues to provide either temporary or permanent transgene expression while avoiding immunosurveillance. This technology has long been appealing because of its superiority over conventional strategies. Viruses can serve as ideal delivery vehicles mainly owing to their native tropism ─ the ability to enter cells efficiently and gain access even to those hard-to-reach ones. Viral vectors are tailored according to different applications but usually share a few key properties of low toxicity, stability, and cell type specificity. With all these advantages, viral vector based gene therapy can be adopted to regulate gene expression so as to provide another option for the treatment of multiple diseases, such as metabolic, cardiovascular, muscular, hematologic, ophthalmologic diseases and cancer. To date, 5 main classes of viral vectors have successfully gone through clinical testing. These include adeno-associated viruses (AAV), adenoviruses (AV), retroviruses (RV), herpes simplex viruses (HSV), and lentiviruses (LV). The contemporary era witnesses the summit of years of biological and medical explorations of viral vector based gene therapy, but still with a pile of problems confronting. And to tackle these problems, vector engineering is becoming a growing focus for the DNA sequence of the viral vector itself influences numerous aspects of a gene therapy’s performance. There are roughly two aims of vector engineering: decreasing immunogenicity and improving transgene expression. Codon optimization is a tactic to archive both goals, in which alternations in the vector’s DNA sequence are explored to eliminate immunogenic sequence motifs while optimizing the transgene for more powerful expression. Subtle changes in vector sequence obtained in this way can have surprising effects and possibly extend the duration of expression for multiple years. Transgene expression can be further programmed by engineering regulatory elements into the vector sequence. Some regulatory elements turn on transgene expression only in certain cell types or tissues to prevent potentially toxic expression in other contexts. Such regulatory elements have become increasingly common in viral vector based gene therapy. Finally, a more distant but attracting goal is to engineer vectors that are inducible, where transgene expression can be controlled using an additional signal, for instance, an orally administered small molecule drug. This could allow clinicians to turn on, turn off, or otherwise adjust a gene therapy after it is administered, delivering a personalized course of treatment. Viral vector based gene therapy is undoubtedly a technology with exciting prospects. To usher in the next generation of viral vector development, efforts will therefore be needed to maintain a careful balance by accelerating programs today while retaining the flexibility to adopt innovative technologies that unlock treatments for common diseases and the full promise of viral vector based gene therapy in the long term.