Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1.

TitleAntisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1.
Publication TypeJournal Article
Year of Publication2022
AuteursBenichou, SAit, Jauvin, D, De Serres-Bérard, T, Pierre, M, Ling, KK, C Bennett, F, Rigo, F, Gourdon, G, Chahine, M, Puymirat, J
JournalGene Ther
Date Published2022 Jan 25

Myotonic dystrophy, or dystrophia myotonica type 1 (DM1), is a multi-systemic disorder and is the most common adult form of muscular dystrophy. It affects not only muscles but also many organs, including the brain. Cerebral impairments include cognitive deficits, daytime sleepiness, and loss of visuospatial and memory functions. The expression of mutated transcripts with CUG repeats results in a gain of toxic mRNA function. The antisense oligonucleotide (ASO) strategy to treat DM1 brain deficits is limited by the fact that ASOs do not cross the blood-brain barrier after systemic administration, indicating that other methods of delivery should be considered. ASO technology has emerged as a powerful tool for developing potential new therapies for a wide variety of human diseases, and its potential has been proven in a recent clinical trial. Targeting DMPK mRNA in neural cells derived from human induced pluripotent stem cells obtained from a DM1 patient with the IONIS 486178 ASO abolished CUG-expanded foci, enabled nuclear redistribution of MBNL1/2, and corrected aberrant splicing. Intracerebroventricular injection of the IONIS 486178 ASO in DMSXL mice decreased the levels of mutant DMPK mRNAs by up to 70% throughout different brain regions. It also reversed behavioral abnormalities following neonatal administration. The present study indicated that the IONIS 486178 ASO targets mutant DMPK mRNAs in the brain and strongly supports the feasibility of a therapy for DM1 patients based on the intrathecal injection of an ASO.

Alternate JournalGene Ther
PubMed ID35075265
Grant ListMOP-111072 and MOP-130373 / / Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) /
USAMRAA W81XWH-21-1-0426 / / U.S. Department of Defense (United States Department of Defense) /
21438 / / AFM-Téléthon (French Muscular Dystrophy Association) /
417929 / / Muscular Dystrophy Association (Muscular Dystrophy Association Inc.) /