Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression.

Autor: Starikova AV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Skopenkova VV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Polikarpova AV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Reshetov DA; Research Centre for Genetic Medicine, Moscow, Russia, 117292., Vassilieva SG; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Velyaev OA; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Shmidt AA; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Savchenko IM; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334., Soldatov VO; Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia, 308007.; Institute of Gene Biology, Core Facility Centre, Russian Academy of Sciences, Moscow, Russia, 119334., Egorova TV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334. egorovatv@genebiology.ru.; Marlin Biotech LLC, Sochi, Russia, 354340. egorovatv@genebiology.ru., Bardina MV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia, 119334.; Marlin Biotech LLC, Sochi, Russia, 354340.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Jan 17; Vol. 12 (1), pp. 848. Date of Electronic Publication: 2022 Jan 17.
DOI: 10.1038/s41598-022-04892-x
Abstrakt: High expectations have been set on gene therapy with an AAV-delivered shortened version of dystrophin (µDys) 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 (µUtrn) as a less immunogenic functional dystrophin substitute for gene therapy. In the current study, we created a human codon-optimized µUtrn which was subjected to side-by-side characterization with previously reported mouse and human µUtrn sequences after rAAV9 intramuscular injections in mdx mice. Long-term studies with systemic delivery of rAAV9-µUtrn 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 µDys. An extensive toxicity study in wild-type rats did not reveal adverse changes associated with high-dose rAAV9 administration and human codon-optimized µUtrn overexpression. Furthermore, we verified that muscle-specific promoters MHCK7 and SPc5-12 drive a sufficient level of rAAV9-µUtrn expression to ameliorate the dystrophic phenotype in mdx mice. Our results provide ground for taking human codon-optimized µUtrn combined with muscle-specific promoters into clinical development as safe and efficient gene therapy for DMD.
(© 2022. The Author(s).)
Databáze: MEDLINE
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