Researchers from Dyne Therapeutics have developed a targeted oligonucleotide delivery system designed to improve treatment for myotonic dystrophy type 1 (DM1). The FORCE platform uses an antigen-binding fragment (Fab) specific to the human transferrin receptor 1 (TfR1) conjugated to an antisense oligonucleotide (ASO) via a cleavable valine-citrulline linker. The approach facilitates the uptake of ASOs into muscle tissue, potentially improving their effectiveness.
The authors wrote, “Oligonucleotides are endocytosed in a non-specific manner when delivered in unconjugated form or via mechanisms that require membrane destabilization, leading toa narrow therapeutic index. Antibody–oligonucleotide conjugates are being explored as alternatives to unconjugated strategies. We selected the Fab format for the FORCE platform because of the superior efficacy of FDC compared to ADC in skeletal muscle.”
DM1 is caused by extra repeats of specific genetic sequences in the DMPK gene, leading to the sequestration of splicing proteins and widespread transcript misprocessing, known as spliceopathy. This leads to problems in muscle tissue, including weakness and dysfunction. While antisense oligonucleotides (ASOs) can help by reducing DMPK RNA levels, delivering them efficiently to muscle cells is challenging because of poor uptake of the molecules.
In preclinical mouse models of DM1, a FORCE-based therapy (DYNE-101) was found to reduce levels of DMPK RNA and improve markers of muscle function compared to the traditional approach. Researchers also tested the therapy in muscle cells derived from DM1 patients – showing that the therapy lowered toxic RNA levels and corrected gene processing errors associated with the disease.
Additional studies were conducted in cynomolgus monkeys, confirming that the therapy could persist in muscle tissues longer than traditional ASOs. This suggests that less frequent dosing may be needed for effective treatment. The authors concluded, “Collectively, these data support the notion that DYNE-101 can improve the underlying spliceopathy in individuals with DM1 and provide functional benefit.”
If successful in human trials, the approach could be expanded to other muscle-related conditions.
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