Table 1.
Gene therapy experiments in murine models of methylmalonic acidemia
| Vector | Dose | MMA Murine Model Tested (Phenotype) | Promoter | cDNA/mRNA | Outcomes | Reference |
|---|---|---|---|---|---|---|
| Ad5 | 3.3 × 108 PFUs/pup | Mmut−/− (neonatal lethal) | CMV | Mmut | Increased survival, decreased pMMA | Chandler and Venditti24 |
| Lentivirus (HIV-1) | 130 μg p24 equivalent of HIV-1 | Mmut−/−MMUTh2 (hypomorph) | EF1α | Codon-optimized MMUT mRNA | Improved growth, decreased pMMA | Wong et al.38 |
| rAAV8 | 1–2 × 1011 vg/pup | Mmut−/− (neonatal lethal) | CBA | Mmut | Increased survival, decreased pMMA | Chandler and Venditti27 |
| rAAV8 | 2–4 × 1011 vg/pup | Mmut−/− (neonatal lethal) | TBG | Mmut | Increased survival, decreased pMMA | Carrillo-Carrasco et al.3 |
| rAAV8 | 1 × 109–1011 vg/pup | Mmut−/− (neonatal lethal) | CBA | MMUT | Increased survival, decreased pMMA | Chandler and Venditti31 |
| rAAV9/rAAV2 | 1 × 1010 vg/pup | Mmut−/− (neonatal lethal) | CBA | Mmut | Increased survival, decreased pMMA | Senac et al.29 |
| rAnc80/rAAV8 | 5 × 1012 vg/kg | Mmut−/−;TgINS-MCK-Mmut (hypomorph) | hAAT | Codon-optimized MMUT | Improved growth, decreased pMMA | Li et al.44 |
| rAAV8 | 5 × 1012 vg/kg | Mut−/−;TgINS-MCK-Mmut (hypomorph) | CBA | Codon-optimized MMUT | Improved growth, decreased pMMA, decreased Fgf21 | Manoli et al.15 |
| rAAV-DJ | 8.6 × 1011–2.5 × 1012 vg/pup | Mmut−/− (neonatal lethal) Mut−/−;TgINS-MCK-Mmut (hypomorph) | Promoterless GeneRide™ | Codon-optimized MMUT | Increased survival, decreased pMMA | Chandler et al.52 |
| rAAV44.9 | 1 × 1011 vg/pup; 1 × 1011 vg/kg | Mmut−/− (neonatal lethal) Mmut−/−;TgINS-MCK-Mmut (hypomorph) | CBA | MMUT | Increased survival, improved growth, decreased pMMA | Di Pasquale et al.42 |
| rAnc80 SVP-Rapa |
2.5 × 1012 vg/kg | Mmut−/−;TgINS-MCK-Mmut (hypomorph) | hAAT | MMUT | Improved growth, decreased pMMA, repeat-dosing | Li et al.40; Ilyinskii et al.41 |
| LNP | 0.2–0.5 mg/kg | Mmut−/−;TgINS-MCK-Mmut (hypomorph) | None | Codon-optimized MMUT mRNA | Improved growth, decreased pMMA | An et al.19; DeRosa et al.43 |
AAV, adeno-associated virus; CBA, cytomegalovirus enhancer chicken beta-actin promoter; CMV, cytomegalovirus immediate-early enhancer and promoter; hAAT, APOE enhancer human alpha-1 antitrypsin; HIV-1, human immunodeficiency virus type 1; LNP, liponanoparticle; MCK, muscle creatine kinase; Mmut, murine methylmalonyl-CoA mutase; MMUT, human murine methylmalonyl-CoA mutase; pMMA, plasma methylmalonic acid; PFUs, plaque-forming units; rAAV, recombinant adeno-associated virus; rAAV8, rAAV serotype 8; vg, vector genomes; TBG, thyroid hormone-binding globulin.