| First Author | Starikova AV | Year | 2022 |
| Journal | Sci Rep | Volume | 12 |
| Issue | 1 | Pages | 848 |
| PubMed ID | 35039573 | Mgi Jnum | J:328182 |
| Mgi Id | MGI:6865133 | Doi | 10.1038/s41598-022-04892-x |
| Citation | Starikova AV, et al. (2022) Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. Sci Rep 12(1):848 |
| abstractText | High expectations have been set on gene therapy with an AAV-delivered shortened version of dystrophin (microDys) for Duchenne muscular dystrophy (DMD), with several drug candidates currently undergoing clinical trials. Safety concerns with this therapeutic approach include the immune response to introduced dystrophin antigens observed in some DMD patients. Recent reports highlighted microutrophin (microUtrn) as a less immunogenic functional dystrophin substitute for gene therapy. In the current study, we created a human codon-optimized microUtrn which was subjected to side-by-side characterization with previously reported mouse and human microUtrn sequences after rAAV9 intramuscular injections in mdx mice. Long-term studies with systemic delivery of rAAV9-microUtrn demonstrated robust transgene expression in muscles, with localization to the sarcolemma, functional improvement of muscle performance, decreased creatine kinase levels, and lower immunogenicity as compared to microDys. An extensive toxicity study in wild-type rats did not reveal adverse changes associated with high-dose rAAV9 administration and human codon-optimized microUtrn overexpression. Furthermore, we verified that muscle-specific promoters MHCK7 and SPc5-12 drive a sufficient level of rAAV9-microUtrn expression to ameliorate the dystrophic phenotype in mdx mice. Our results provide ground for taking human codon-optimized microUtrn combined with muscle-specific promoters into clinical development as safe and efficient gene therapy for DMD. |
