Table 1.
Molecular analyses of gene therapy treated PahΔexon1/Δexon1 and pahenu2/enu2 mice. Pre- and post- gene therapy (GT) effects in a dose escalation experiment in PahΔexon1/Δexon1 mice, as well as gene addition therapy in pahenu2/enu2 animals. The first column indicates the gene therapy administered, including dose and transgene, where rAAV2/8 LSPmPAH indicates a therapeutic virus containing an rAAV2 genome with a transgene cassette containing a Liver Specific Promoter driving murine PAH packaged into an AAV8 capsid. The AAV2/8 LSPmPAHfs contains a frameshift and is used as a control vector.
| Gene therapy | Blood Phe Pre- GT (μM) |
Blood Phe Post-GT (μM) |
Blood Tyr Pre- GT (μM) |
Blood Tyr Post-GT (μM) |
Brain Phe Post-GT (μM) |
Brain Tyr Post-GT (μM) |
Liver PAH activity (%WT) |
Vg copy/liver diploid genome |
|---|---|---|---|---|---|---|---|---|
| PahΔexon1/Δexon1 mice | ||||||||
| 1E12 AAV2/8 LSPmPAHfs female | 2193 | 1928 | 38 | 37 | 1222 | 116 | 0.2% | 1.0 |
| 1E10 AAV2/8 LSPmPAH male | 3095 | 235 | 48 | 117 | 325 | 161 | 4.8% | 2.9 |
| 1E11 AAV2/8 LSPmPAH female | 2677 | 195 | 45 | 115 | 135 | 135 | 42% | 16.2 |
| 1E12 AAV2/8 LSPmPAH male | 1835 | 127 | 56 | 132 | 382 | 160 | 96.1% | 50 |
| pahenu2/enu2 mice | ||||||||
| 1E11 AAV2/8 LSPmPAH 3 male/3 female | 1983 ± 540a | 176 ± 52a | ND | ND | ND | ND | 7.7 ± 2.2%a | 8-42b |
| 1E12 AAV2/8 LSPmPAH 3 male/3 female | 1921 ± 603a | 99 ± 22a | ND | ND | ND | ND | 14.8 ± 3.3%a | 56-291b |
ND – not done.
a
Mean ± SD.
b
Range.