Table 2.

Relative pros and cons of viral versus non‐viral vectors

Consideration	Viral vectors	Non‐viral vectors
Transduction efficiency	Comparatively good	Comparatively poor; a key limitation for non‐viral vectors.
Persistence of expression	Years and perhaps patient's lifetime; double‐edged sword vis‐à‐vis reversibility.	Generally shorter than with virally administered transgenes; repeated dosing will be required except for mechanisms of action that are permanent (e.g., gene editing)
Reversibility of effect	Not clinically possible, although technical solutions exist that could be developed, depending on mechanism of action (e.g., protein replacement vs. permanent gene editing mechanism).	A strength for the use of non‐viral vectors, depending on mechanism of action (e.g., protein replacement vs. permanent gene editing mechanism).
Ability to titrate dose to effect in patient	Not possible; dose required for effectiveness is difficult to predict; requires applications with a large therapeutic window between the minimally effective dose and the maximally tolerated dose.	A strength for the use of non‐viral vectors, although relationship between dose and effect must be empirically established.
Possibility for repeated dosing	Immune response to first dosing may limit effectiveness or prohibit use of an additional administrations of the same viral serotype.	Comparatively better, though an immune response to novel transgene product may still pose a limitation.
Risk of insertional mutagenesis	Not an issue for AAV; minimized in newer generations of lentivirus.	Non‐existent to minimal, depending mechanism of action (e.g., transposons can insert DNA into unpredictable host chromosome locations).
For diseases with central nervous system (CNS) involvement:
CNS distribution via axonal transport	Comparatively good to excellent (a feature of many AAV serotypes).	Comparatively poor to non‐existent.
Neuronal specificity	A feature of some AAV serotypes; can be useful for avoiding immune response in nervous system mediated by glial cells.	Carriers with neuronal specificity remain to be developed.
Crossing of the blood‐brain barrier	A feature of some AAV serotypes; further developments needed for clinical utility.	Requires nanoparticles with peptides or other conjugates for uptake across BBB; decades of research have not yet yielded clinically deployable solution.