FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models
Abstract Background We developed the FORCETM platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated...
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Nature Portfolio
2025-01-01
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| Series: | Communications Medicine |
| Online Access: | https://doi.org/10.1038/s43856-025-00733-w |
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| author | Timothy Weeden Tyler Picariello Brendan Quinn Sean Spring Pei-Yi Shen Qifeng Qiu Benjamin F. Vieira Lydia Schlaefke Ryan J. Russo Ya-An Chang Jin Cui Monica Yao Aiyun Wen Nelson Hsia Tama Evron Katy Ovington Pei-Ni Tsai Nicholas Yoder Bo Lan Reshmii Venkatesan John Hall Cody A. Desjardins Mo Qatanani Scott Hilderbrand John Najim Zhenzhi Tang Matthew K. Tanner Romesh Subramanian Charles A. Thornton Oxana Ibraghimov-Beskrovnaya Stefano Zanotti |
| author_facet | Timothy Weeden Tyler Picariello Brendan Quinn Sean Spring Pei-Yi Shen Qifeng Qiu Benjamin F. Vieira Lydia Schlaefke Ryan J. Russo Ya-An Chang Jin Cui Monica Yao Aiyun Wen Nelson Hsia Tama Evron Katy Ovington Pei-Ni Tsai Nicholas Yoder Bo Lan Reshmii Venkatesan John Hall Cody A. Desjardins Mo Qatanani Scott Hilderbrand John Najim Zhenzhi Tang Matthew K. Tanner Romesh Subramanian Charles A. Thornton Oxana Ibraghimov-Beskrovnaya Stefano Zanotti |
| author_sort | Timothy Weeden |
| collection | DOAJ |
| description | Abstract Background We developed the FORCETM platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression. Methods Multiple surrogate conjugates were generated to characterize the FORCE platform. DYNE-101 is the conjugate designed to target DMPK and correct spliceopathy for the treatment of DM1. HSALR and TfR1 hu/mu ;DMSXL Tg/Tg mice were used as models of myotonic dystrophy, the latter expresses human TfR1 and a human DMPK RNA with >1,000 CUG repeats. Cynomolgus monkeys were used to determine translatability of DYNE-101 pharmacology to higher species. Results In HSALR mice, a surrogate FORCE conjugate achieves durable correction of spliceopathy and improves myotonia to a greater extent than unconjugated ASO. In patient-derived myoblasts, DYNE-101 reduces DMPK RNA and nuclear foci, consequently improving spliceopathy. In TfR1 hu/mu ;DMSXL Tg/Tg mice, DYNE-101 reduces mutant DMPK RNA in muscle, thereby correcting splicing. Reduction of DMPK foci in cardiomyocyte nuclei accompanies these effects. Low monthly dosing of DYNE-101 in TfR1 hu/mu ;DMSXL WT/Tg mice or cynomolgus monkeys leads to a profound reduction of DMPK expression in muscle. Conclusions These data validate FORCE as a drug delivery platform and support the notion that DM1 may be treatable with low and infrequent dosing of DYNE-101. |
| format | Article |
| id | doaj-art-89332c5c02314f788c350eed21f27744 |
| institution | Kabale University |
| issn | 2730-664X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Communications Medicine |
| spelling | doaj-art-89332c5c02314f788c350eed21f277442025-01-19T12:36:57ZengNature PortfolioCommunications Medicine2730-664X2025-01-015111810.1038/s43856-025-00733-wFORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical modelsTimothy Weeden0Tyler Picariello1Brendan Quinn2Sean Spring3Pei-Yi Shen4Qifeng Qiu5Benjamin F. Vieira6Lydia Schlaefke7Ryan J. Russo8Ya-An Chang9Jin Cui10Monica Yao11Aiyun Wen12Nelson Hsia13Tama Evron14Katy Ovington15Pei-Ni Tsai16Nicholas Yoder17Bo Lan18Reshmii Venkatesan19John Hall20Cody A. Desjardins21Mo Qatanani22Scott Hilderbrand23John Najim24Zhenzhi Tang25Matthew K. Tanner26Romesh Subramanian27Charles A. Thornton28Oxana Ibraghimov-Beskrovnaya29Stefano Zanotti30Dyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncDyne Therapeutics IncUniversity of Rochester Medical CenterUniversity of Rochester Medical CenterDyne Therapeutics IncUniversity of Rochester Medical CenterDyne Therapeutics IncDyne Therapeutics IncAbstract Background We developed the FORCETM platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression. Methods Multiple surrogate conjugates were generated to characterize the FORCE platform. DYNE-101 is the conjugate designed to target DMPK and correct spliceopathy for the treatment of DM1. HSALR and TfR1 hu/mu ;DMSXL Tg/Tg mice were used as models of myotonic dystrophy, the latter expresses human TfR1 and a human DMPK RNA with >1,000 CUG repeats. Cynomolgus monkeys were used to determine translatability of DYNE-101 pharmacology to higher species. Results In HSALR mice, a surrogate FORCE conjugate achieves durable correction of spliceopathy and improves myotonia to a greater extent than unconjugated ASO. In patient-derived myoblasts, DYNE-101 reduces DMPK RNA and nuclear foci, consequently improving spliceopathy. In TfR1 hu/mu ;DMSXL Tg/Tg mice, DYNE-101 reduces mutant DMPK RNA in muscle, thereby correcting splicing. Reduction of DMPK foci in cardiomyocyte nuclei accompanies these effects. Low monthly dosing of DYNE-101 in TfR1 hu/mu ;DMSXL WT/Tg mice or cynomolgus monkeys leads to a profound reduction of DMPK expression in muscle. Conclusions These data validate FORCE as a drug delivery platform and support the notion that DM1 may be treatable with low and infrequent dosing of DYNE-101.https://doi.org/10.1038/s43856-025-00733-w |
| spellingShingle | Timothy Weeden Tyler Picariello Brendan Quinn Sean Spring Pei-Yi Shen Qifeng Qiu Benjamin F. Vieira Lydia Schlaefke Ryan J. Russo Ya-An Chang Jin Cui Monica Yao Aiyun Wen Nelson Hsia Tama Evron Katy Ovington Pei-Ni Tsai Nicholas Yoder Bo Lan Reshmii Venkatesan John Hall Cody A. Desjardins Mo Qatanani Scott Hilderbrand John Najim Zhenzhi Tang Matthew K. Tanner Romesh Subramanian Charles A. Thornton Oxana Ibraghimov-Beskrovnaya Stefano Zanotti FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models Communications Medicine |
| title | FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models |
| title_full | FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models |
| title_fullStr | FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models |
| title_full_unstemmed | FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models |
| title_short | FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models |
| title_sort | force platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models |
| url | https://doi.org/10.1038/s43856-025-00733-w |
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