Possible strategies to overcome capsid-specific T-cell responses
| Strategy . | Advantages . | Disadvantages . |
|---|---|---|
| Select subjects naive to AAV. | Avoid memory responses to AAV. | Data suggest that capsid-reactive T cells fail to circulate in peripheral blood, and thus the most reliable way to screen subjects for T-cell reactivity to AAV is to use splenocytes,85 an approach not feasible clinically. |
| Decrease the therapeutic vector dose using highly efficient AAV vectors4 of hyperactive variants of the therapeutic transgenes.110,111 | Available data suggest that the approach is feasible and may be effective in preventing T-cell–mediated clearance of transduced cells. | This strategy may not be applicable for those gene transfer protocols in which the therapeutic dose is expected to be considerably higher than the doses tested so far in humans. |
| Hyperactive variants are not available for every transgene. | ||
| Administer IS to prevent or block T-cell responses to AAV. | Steroids effectively block T-cell responses directed against the AAV capsid at doses tested thus far; | Potential risks associated with systemic IS; |
| Risks associated with blocking the induction of regulatory T cells with IS67,91 ; | ||
| Extensive experience with IS comes from transplant medicine, and several IS drugs can be safely administered for prolonged periods. | Many IS drugs, particularly biologics, are not effective in animal models, precluding preclinical testing; | |
| Timing of capsid presentation on MHC I in vivo is unknown, and thus timing of IS administration may be difficult to define except through clinical experience. | ||
| Switch AAV serotypes56 or engineer AAV capsids to remove MHC I epitopes. | In theory, the approach could work. | Because of AAV capsid sequence conservation, a high degree of cross-recognition by capsid-specific T cells is expected67 ; |
| Switching or altering the capsid can significantly modify the AAV capsid tissue tropism; | ||
| Complexity of MHC I recognition in humans and presence of subdominant T-cell epitopes may hinder efforts in this direction. | ||
| Use proteasome inhibitors91 or mutant capsids that are not efficiently ubiquitinated.94 | Both measures have shown efficacy in reducing AAV capsid antigen presentation on MHC I. | The effect may be only partial or may require prolonged pharmacotherapy. |
| Strategy . | Advantages . | Disadvantages . |
|---|---|---|
| Select subjects naive to AAV. | Avoid memory responses to AAV. | Data suggest that capsid-reactive T cells fail to circulate in peripheral blood, and thus the most reliable way to screen subjects for T-cell reactivity to AAV is to use splenocytes,85 an approach not feasible clinically. |
| Decrease the therapeutic vector dose using highly efficient AAV vectors4 of hyperactive variants of the therapeutic transgenes.110,111 | Available data suggest that the approach is feasible and may be effective in preventing T-cell–mediated clearance of transduced cells. | This strategy may not be applicable for those gene transfer protocols in which the therapeutic dose is expected to be considerably higher than the doses tested so far in humans. |
| Hyperactive variants are not available for every transgene. | ||
| Administer IS to prevent or block T-cell responses to AAV. | Steroids effectively block T-cell responses directed against the AAV capsid at doses tested thus far; | Potential risks associated with systemic IS; |
| Risks associated with blocking the induction of regulatory T cells with IS67,91 ; | ||
| Extensive experience with IS comes from transplant medicine, and several IS drugs can be safely administered for prolonged periods. | Many IS drugs, particularly biologics, are not effective in animal models, precluding preclinical testing; | |
| Timing of capsid presentation on MHC I in vivo is unknown, and thus timing of IS administration may be difficult to define except through clinical experience. | ||
| Switch AAV serotypes56 or engineer AAV capsids to remove MHC I epitopes. | In theory, the approach could work. | Because of AAV capsid sequence conservation, a high degree of cross-recognition by capsid-specific T cells is expected67 ; |
| Switching or altering the capsid can significantly modify the AAV capsid tissue tropism; | ||
| Complexity of MHC I recognition in humans and presence of subdominant T-cell epitopes may hinder efforts in this direction. | ||
| Use proteasome inhibitors91 or mutant capsids that are not efficiently ubiquitinated.94 | Both measures have shown efficacy in reducing AAV capsid antigen presentation on MHC I. | The effect may be only partial or may require prolonged pharmacotherapy. |