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

Abstract

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.

Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

“…Recent reports showed that the delivery of the DMPK -specific AON in DMSXL mice via intracerebroventricular injections reverses behavioral defects [ 54 ]. The development of this approach might lead to clinical studies, addressing correction of CNS defects in DM1.…”

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

“…Notably, IONIS screened hundreds of cEt-modified gapmer ASOs in human skeletal muscle cells to identify sequences leading to DMPK mRNA knockdown, followed by in vivo evaluation of their tolerability in mice and rats [ 63 ]. These results led to the identification of IONIS 486178 (or ISIS 486178), which has been extensively investigated in DM1 mice models [ 64 , 65 , 66 , 67 ]. In vitro screening is an important step in the development of antisense therapy, which requires accurate models to identify the best drug candidates.…”

“…Treatments of DM1 myotubes derived from immortalized myoblasts, MyoD-induced fibroblasts, or hiPSCs with (CAG)7 ASOs with PS and 2′-O-Me modifications have been shown to successfully decrease foci formation and, in some cases, partially reverse mis-splicing defects, supporting the utility of these models for ASOs screening [ 71 , 72 , 73 , 74 ]. Differentiation of infantile DM1 hiPSCs into neural progenitor cells has also been achieved to validate the use of IONIS 486178 for rescuing MBNL sequestration by foci and neuronal alternative splicing defects [ 65 ]. Since splicing dysregulation in DM1 mainly involve biased production of fetal isoforms in adult tissues, insufficient maturation of in vitro differentiated cells may hinder the detection of alternative splicing correction by ASOs [ 72 , 75 ].…”

“…Notably, we have reported that both the cEt gapmer (ISIS 486178) and C16-HA ASOs (IONIS-877864) do not reach the brain following subcutaneous injection [ 64 , 66 ]. To overcome this limitation, we recently injected IONIS 486178 by intracerebroventricular injection in DMSXL mice and succeeded in destroying up to 70% of DMPK mRNAs in multiple brain areas [ 65 ]. Intrathecal administration of the ASO nusinersen has been approved by the FDA for clinical use to treat SMA, further supporting the feasibility of this approach in humans [ 127 ].…”

Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics

“…While the first attempt to reduce DM1 pathology with the DMPK1 -specific AON in a clinical trial for adult DM1 was not successful due to the low penetration of AON in skeletal muscle, studies on the improvement of this approach continue. More importantly, preclinical studies in DM1 showed that AONs were beneficial not only for the skeletal muscle pathology, but that they could also reduce cognitive defects and reverse cardiac phenotypes [ 12 , 14 , 15 ]. As described in Dr. Mahadevan’s review, which focused on cardiac pathology in DM [ 12 ], the application of the DMPK -specific AON in the preclinical study using a tet-inducible DM1 mouse model, expressing the 3′UTR of DMPK with 200 CUG repeats, reduced skeletal and cardiac muscle deficiencies [ 12 , 15 ].…”