Table 3. Effects of gene therapy on cardiovascular system in the Mucopolysaccharidoses.
| Disease | Vector | Administration route | Model and age at administration | Endpoint (time post-injection) | Results in the heart | Other remarks | Reference | |
|---|---|---|---|---|---|---|---|---|
| Increase in enzyme activity | Substrate reduction | |||||||
| MPS I | non-viral vectors | Hydrodinamic injection, subcutaneous | mice, adult | variable | Yes | Yes | Use of Sleeping Beauty transposon, DNA minicircle and microencapsulated cells | (Aronovich et al., 2009; Lizzi Lagranha et al., 2017; Osborn et al., 2011) |
| AAV | IV, temporal vein | mice, 1 day | 5 months | Yes | Yes | (Hartung et al., 2004) | ||
| IV, cephalic vein | cats, 3-5 months | 6 months | Yes | Yes | Correction of storage lesions in aorta and myocardium, amelioration of aortic valve disease | (Hinderer et al., 2014) | ||
| LV | IV, tail vein | mice, 8-10 weeks | 1 month | Yes | Yes | Lentiviral vector elicited low immune response, increasing further at later time points | (Di Domenico et al., 2005) | |
| IV, temporal vein | mice, 1 day | 20 weeks | Yes | Yes | Newborn mice responded better to treatment | (Kobayashi et al., 2005) | ||
| RV | IV, temporal or tail vein | mice, 6 weeks | 8 months-old # | Yes | Yes | Reduced GAG in aortic valves and heart, but not in the aorta. Most RV-treated mice had elastic fiber fragmentation and aortic dilatation. Aorta had slight increase in IDUA activity, but not enough to prevent aortic disease. 56% of RV treated mice had aortic insufficiency. | (Ma et al., 2007) | |
| IV, temporal vein | mice, 6 weeks | 8 months-old # | Yes | Yes | Aortas remained dilated, with marked GAG storage, and 75% of treated mice had aortic insufficiency. | (Herati et al., 2008) | ||
| IV, temporal vein | mice, 2-3 days | 8 months | Yes | Yes | Prevented aortic dilatation and insuficiency. No significant changes in left ventricular wall thickness, mass index or end-diastolic chamber size. Fractional shortening was significantly greater in high-dose RV mice. | (Liu et al., 2005) | ||
| IV, jugular vein | dogs, 2-3 days | up to 21 months | Yes | Yes | Reduction of aortic diameter, reduced mitral valve thickening and reduced elastic fiber fragmentation of aorta. | (Traas et al., 2007) | ||
| ex vivo RV | IV, tail vein | mice, 6-8 weeks | 8 months | Low | No | BMT with RV-modified cells. One mice presented restoration of left ventricular function and normalization of myocites storage vacuoles. | (Jordan et al., 2005) | |
| ex vivo LV | mice, 2 months | 6 months | Yes | Yes | BMT with LV-modified cells. | (Visigalli et al., 2010) | ||
| MPS II | plasmid | electro gene transfer on quadriceps | mice, 12-16 weeks | 5 weeks | No | No | Transduction was restricted to injection site, had no effect of the heart | (Friso et al., 2008) |
| AAV | IV, tail vein | mice, 2 months | 1 and 7 months | Yes | Yes | (Cardone et al., 2006) | ||
| IV, tail vein | mice, 20 weeks | 6 and 24 weeks | Yes | Yes | (Jung et al., 2010) | |||
| AAV9 | Intrathecal | Mice, 2 months | 4 months | Yes | Yes | Complete correction of storage lesions in heart, but possibly due to cross-correction from the serum enzyme | (Motas et al., 2016) | |
| ICV | Mice, 2 months | 40 weeks | Yes | Yes | Pilot study compared different routes (intrathecal intravenous and intracerebroventricular). | (Laoharawee et al., 2017) | ||
| ICV | Mice, 2-3 months | 3 weeks | NA | Partial | ||||
| ex vivo LV | IV | mice, 9 weeks | 24 weeks | Yes | Yes | BMT with LV modified cells | (Wakabayashi et al., 2015) | |
| MPS IVA | AAV | IV | mice, NS | 12 weeks | Yes | NA | (Tomatsu et al., 2012) | |
| MPS VI | AAV | IV and IM | cats and rats, newborn | 6 months (rat) and 1 year (cat) | Yes | Yes | Vector spread to heart after both IM and IV injections for both animal models | (Tessitore et al., 2008) |
| IV, temporal or femoral vein | rats 5 and 30 days | 6-7 months | Yes | Yes | Pre-treatment with immunosupressionperformed. Heart valve GAG storage was reduced in pre-treated animals. | (Cotugno et al., 2010) | ||
| IV, jugular or cephalic vein | cats, 5 and 50 days | 12 months | NA | NA | Reduced or normalized mitral valve thickening independent of age of treatment | (Cotugno et al., 2011) | ||
| IV, retro-orbital | mice, 30 days | 6 or 12 months | NA | Yes | Reduced GAG storage in aortic valves and myocardium | (Ferla et al., 2014) | ||
| IV, retro-orbital | Mice, 30 days | 6 months | Yes | Yes | Combined low vector dose with monthly ERT infusions | (Alliegro et al., 2016) | ||
| IV | Mice, adult | 6 months | NA | Yes | Described safety of the therapy. Minimal GAG reduction in heart valves. | (Ferla et al., 2017) | ||
| RV | IV, jugular vein | cats, newborn | 6 months to 8 years | Yes | Yes | Supraphysiologic ARSB levels on the bloodstream, but only 9-85% of normal in heart and aorta of treated cats. Treated cats had significant reduced mitral valve thickening, but still developed aortic dilatation, aortic valve regurgitation and thickened aortic valve leaflets. | (Ponder et al., 2012) | |
| MPS VII | AAV | IV, temporal vein | mice, 2 days | 16 weeks | Yes | NA | (Daly et al., 1999) | |
| Intrahepatic injection | mice, 7-8 weeks | 24 weeks | Yes | Yes | (Sferra et al., 2004) | |||
| LV | IV, temporal vein | mice, 2 days | 12 or 18 months | Yes | Yes | Used two MPS VII mouse strains. | (Derrick-Roberts et al., 2014) | |
| LV | IV, tail vein | Mice, 4 months | 2 months | Partial | Partial | GAG storage in heart only stabilized but not normalized after treatment. | (Derrick-Roberts et al., 2016) | |
| RV | IV, tail vein | mice, 5-7 weeks | 3 months | Partial | No | Mice were pre-treated with AV-CMV-HGF in the quadriceps. Treatment increased only 5% of GUSB activity in heart | (Gao et al., 2000) | |
| IV, jugular vein | dogs, 2-3 days | variable, up to 12 months | Yes | NA | Treated dogs had normal valve thickness, no aortic valve insufficiency, mild mitral regurgitation and aortic diameter within normal limits at 8-9 months of age | (Ponder et al., 2002) | ||
| IV, jugular vein | dogs, 2-3 days | 24 months | Yes | Yes | Treated dogs had mild mitral regurgitation at 4-5 months of age, which improved over time. At 2 years of age, murmurs were absent and valve thickness was normal. Aortic diameter was within normal limits. Treated dogs had mild improvement in GUSB activity and GAG storage in the aorta. | (Sleeper et al., 2004) | ||
| IV, jugular vein | dogs, 2-3 days | variable, up to 8 years | Yes | NA | Aortic dilatation was delayed in RV treated dogs, but it did occur at late times even with stable serum GUSB activity. They presented reduced elastin fragmentation, reduced expression of MMP-12 and of cathepsins B, D, K and S, compared to the untreated group. RV sequences were not found in the aorta. | (Metcalf et al., 2010) | ||
| IV, jugular vein | dogs, 2-3 days | variable, up to 8 years | Yes | Yes | GAG content in the mitral valve of treated dogs at 8 years post injection was lower than untreated dogs, but still higher than the normal. GUSB activity was 25% of normal in the mitral valves. Treatment reduced total cathepsins activity and increased content of intact collagen. | (Bigg et al., 2013) | ||
| IV, temporal vein | mice, 2-3 days | 6 months | Yes | Yes | Aorta GUSB activity in treated animals was 5-fold de value of normal mice and 325-fold de value of the untreated ones. GAG content reduced to 5% of untreated mice, although stil higher than normal. Reduced aortic dilatation but did not prevent it. | (Baldo et al., 2011) | ||
AAV: adeno-associated virus; LV: Lentivirus; RV: retrovirus; IV:intravenous; IM: intramuscular; ICV: intracerebroventricular; BMT: bone marrow transplantation; NA: not analysed; NS: not specified; #Age at analysis