Table 2. Effects of gene therapy on cardiovascular system in Glycogen Storage Diseases (Pompe Disease).
| Vector | Administration route | Model and age at administration | Endpoint (time post-injection) | Results in heart | Other remarks | Reference | ||
|---|---|---|---|---|---|---|---|---|
| Increase in enzyme activity | Substrate reduction | |||||||
| AV | AV-GAA | transmyocardial | rats, newborn | 5-7 days | Yes | Yes | Transduction occured mainly in the liver | (Pauly et al., 1998) |
| [E12, polymerase2] AV-GAA | IV, retroorbital sinus | mice, 3 months | 2-3 days up to 6 months | Yes | Yes | Treatment was more efficient in the first 50 days post injection | (Ding et al., 2001) | |
| mice, 3 months | 180 days | Yes | Yes | Compared GAA-KO/SCID mice with GAA-KO mice, the first had better results | (Xu et al., 2004) | |||
| mice, 12-14 and 17-19 months | 17 days | Yes | Yes | No difference between age groups | (Xu et al., 2005) | |||
| HD-AV | balloon catheter occlusion to liver | Healthy baboon, 6 years | 6 months | Yes | No | High levels of protein in the heart, treatment well tolerated | (Rastall et al., 2016) | |
| AV/AAV | hybrid AV-AAV | Intramuscular | Mice, 3 days | 24 weeks | Yes | Yes | Transduction of the heart rather than cross-correction from other tissues. | (Sun et al., 2003) |
| AAV | AAV1-CMV | IV, superficial temporal vein | mice, 1 day | 11 months | Yes | Yes | (Mah et al., 2005) | |
| AAV2* | intramyocardial* | mice, 8 weeks | 6 weeks | Yes | Yes | (Fraites et al., 2002) | ||
| AAV2/1-CMV | IV, superficial temporal vein | mice, 1 day | 1 year | Yes | Yes | Elongation of PR interval, reduction of left ventricular mass, but mild improvement in correction of cardiac disease | (Mah et al., 2007) | |
| AAV2/7-MCK* | IV, retroorbital sinus | mice, 12 weeks | 24 weeks | Yes | Yes | GAA-KO and GAA-KO/SCID mice | (Sun et al., 2005a) | |
| AAV2/8 | IV, retroorbital sinus | mice, 12 weeks | 24 weeks | Yes | Yes | GAA-KO/SCID mice. Restoration of normal myofiber structure | (Sun et al., 2005b) | |
| AAV2/8-LSP | IV, tail vein | mice, 9–29 weeks | 16 weeks | Yes | Yes | Proved to be safe and well-tolerated. Efficacy was higher in males and at later timepoints | (Wang et al., 2014) | |
| AAV2/8-LSP* | IV, retroorbital sinus | mice, 12 weeks | 12 weeks | Yes | Yes | (Franco et al., 2005) | ||
| AAV2/8-MHCK7* | hydrostatic isolated limb perfusion | mice, 3 months | 18 weeks | Mild | Mild | Good results in skeletal muscles, but not in the heart | (Sun et al., 2010) | |
| AAV2/8-LSPhGAA | IV | mice, adult | 36 weeks | Yes | Yes | Defined the minimum effective dose; prevented IgG formation due to ERT. | (Han et al., 2017) | |
| AAV2/9 -MHCK7* | IV, retroorbital sinus | mice, 3 months | 18 weeks | Yes | Yes | (Sun et al., 2008) | ||
| AAV2/9-CB | IV | mice, 6 months | 12 and 24 weeks | Yes | Yes | Pre-treatment with anti-CD4 mAb enhanced biochemical correction in the heart | (Han et al., 2015) | |
| AAV2/9-CB | IV, tail vein | mice, 4 months | 18 weeks | Yes | Yes | Daily treatment with salmeterol* enhanced biochemical correction observed with AAV treatment | (Han et al., 2016) | |
| AAV5- or AAV8-DHBV | IV, portal vein | mice, 10 weeks | 16 weeks | Yes | Yes | Neonatal pre-treatment with human GAA resulted in greater cardiac correction in mice Ab- for GAA | (Cresawn et al., 2005) | |
| AAV8-DC190 | IV, tail vein | mice, 12 week | 6 months | Yes | Yes | (Ziegler et al., 2008) | ||
| AAV9-DES | IV, jugular vein | mice, 3 months | 3 months | Yes | Yes | Elongation of the PR interval, increased ejection fraction and reduction in left ventricular mass. In comparison, AVV9 treatment increased more GAA activity in the heart than ERT. | (Falk et al., 2015) | |
| AAV9-DES* | intrapleural | mice, 3 months | 6 months | Yes | Yes | Improved cardiac ejection fraction and stroke volume. | (Falk et al., 2013) | |
| AAV9-CAG-hGAA | Intrathecal | Mice, 1 month | 11 months | Yes | Yes | presented reduced thickness of the left ventricular wall, well arranged myofibrils and correction of vacuolation of cardiac fibers due to glycogen storage | (Hordeaux et al., 2017) | |
| Co-packaging of AAV9-LSP with AAV9-DES* | IV, tail vein | mice, 4-6 weeks | 8 weeks | Yes | Yes | Co-packaged AAV9 attenuated pre-existing humoral and cellular immune responses, enhancing biochemical correction | (Doerfler et al., 2016) | |
| LV | LV-CMV-GAA | IV, superficial temporal vein | mice, 1-2 days | 24 weeks | Yes | Yes | (Kyosen et al., 2010) | |
| Ex vivo lentivirus* | IV, retroorbital sinus | mice, 6-8 weeks | 17 weeks | NA | No | HSCT using lentivirus modified HSC | (Douillard-Guilloux et al., 2009) | |
| Ex vivo lentivirus* | IV, tail vein | mice, 8-12 weeks | up to 15 months | Yes | Yes | HSCT using lentivirus modified HSC. Decreased relative right and left ventricular mass with restoration of left ventricular wall thickness. Heart rate normalized. Still poor response compared to in vivo therapy. | (van Til et al., 2010) | |
AV: adenovirus; AAV: adeno-associated virus; LV: Lentivirus; IV:intravenous; IM: intramuscular; BMT: bone marrow transplant; HSC: hematopoietic stem cell; HSCT: hematopoietic stem cell transplant; NA: not analysed; *Results showed restricted to the most effective protocol tested.