Synthetic long non-coding RNAs [SINEUPs] rescue defective gene expression in vivo.
Non-coding RNAs provide additional regulatory layers to gene expression as well as the potential to being exploited as therapeutic tools. Non-coding RNA-based therapeutic approaches have been attempted in dominant diseases, however their use for treatment of genetic diseases caused by insufficient gene dosage is currently more challenging. SINEUPs are long antisense non-coding RNAs that up-regulate translation in mammalian cells in a gene-specific manner, although, so far evidence of SINEUP efficacy has only been demonstrated in in vitro systems. We now show that synthetic SINEUPs effectively and specifically increase protein levels of a gene of interest in vivo. We demonstrated that SINEUPs rescue haploinsufficient gene dosage in a medakafish model of a human disorder leading to amelioration of the disease phenotype. Our results demonstrate that SINEUPs act through mechanisms conserved among vertebrates and that SINEUP technology can be successfully applied in vivo as a new research and therapeutic tool for gene-specific up-regulation of endogenous functional proteins.
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Via Campi Flegrei 34, Pozzuoli (NA), Italy.
Alessia
A
Indrieri
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Via Campi Flegrei 34, Pozzuoli (NA), Italy.
Claudia
C
Grimaldi
Area of Neuroscience, SISSA, 34136, Trieste, Italy.|Dipartimento di Scienze della Salute, Universita' del Piemonte Orientale, Novara, Italy.
Silvia
S
Zucchelli
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Via Campi Flegrei 34, Pozzuoli (NA), Italy.
Roberta
R
Tammaro
Area of Neuroscience, SISSA, 34136, Trieste, Italy.|Department of Neuroscience and Brain Technologies, Italian Institute of Technology, 16163, Genova, Italy.|TransSINE Technologies, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama, Kanagawa 230-0045 Japan.
Stefano
S
Gustincich
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Via Campi Flegrei 34, Pozzuoli (NA), Italy.|Medical Genetics Services, Department of Translational Medicine, Federico II University, 80131, Naples, Italy.
Brunella
B
Franco
D000818:Animals; D001688:Biological Products / Q000008:administration & dosage* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D040181:Genetic Diseases, X-Linked / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008850:Microphthalmos / Q000628:therapy*; D009990:Oryzias; D062085:RNA, Long Noncoding / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D012868:Skin Abnormalities / Q000628:therapy*; D016896:Treatment Outcome
D001688:Biological Products; D062085:RNA, Long Noncoding