Pub Date : 2024-08-29DOI: 10.1016/j.omtn.2024.102296
Maxim V. Berezovski
{"title":"Breaking bad aggregates: How a DNA aptamer cleans up Parkinson’s disease","authors":"Maxim V. Berezovski","doi":"10.1016/j.omtn.2024.102296","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102296","url":null,"abstract":"","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"437 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.omtn.2024.102312
Vijay N. Gulumkar, Steven F. Dowdy
{"title":"Stereopure ASOs: An unanticipated increase in selectivity for targeting mutant HTT","authors":"Vijay N. Gulumkar, Steven F. Dowdy","doi":"10.1016/j.omtn.2024.102312","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102312","url":null,"abstract":"","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"31 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.omtn.2024.102316
Hua Huang, Dong Rui Ma, Derrick Wei Shih Chan, Adeline Seow Fen Ngoh, Dejie Yu, Shi Jun Ng, John Jia En Chua, Eng King Tan, Hui-Lin Chin, Denise Li Meng Goh, Tuck Wah Soong
A missense mutation c.1220C>G of gene was recently identified in an infant with epilepsy. encodes K1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved motif. Functional characterization revealed that mutant K1.2_P407R subunits formed loss-of-function channels and suppressed both K1.2 and K1.1 channel activities. Hetero-tetrameric assembly of the K1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human K1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed K1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.
{"title":"Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy","authors":"Hua Huang, Dong Rui Ma, Derrick Wei Shih Chan, Adeline Seow Fen Ngoh, Dejie Yu, Shi Jun Ng, John Jia En Chua, Eng King Tan, Hui-Lin Chin, Denise Li Meng Goh, Tuck Wah Soong","doi":"10.1016/j.omtn.2024.102316","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102316","url":null,"abstract":"A missense mutation c.1220C>G of gene was recently identified in an infant with epilepsy. encodes K1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved motif. Functional characterization revealed that mutant K1.2_P407R subunits formed loss-of-function channels and suppressed both K1.2 and K1.1 channel activities. Hetero-tetrameric assembly of the K1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human K1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed K1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"43 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.omtn.2024.102315
Camille Huart, Mayuk Saibal Gupta, Jo A. Van Ginderachter
In recent years, the field of epitranscriptomics has witnessed significant breakthroughs with the identification of more than 150 different chemical modifications in different RNA species. It has become increasingly clear that these chemical modifications play an important role in the regulation of fundamental processes linked to cell fate and development. Further interest was sparked by the ability of the epitranscriptome to regulate pathogenesis. However, despite the involvement of macrophages in a multitude of diseases, a clear knowledge gap exists in the understanding of how RNA modifications regulate the phenotype of these cells. Here, we provide a comprehensive overview of the known roles of macrophage RNA modifications in the context of different diseases.
{"title":"The role of RNA modifications in disease-associated macrophages","authors":"Camille Huart, Mayuk Saibal Gupta, Jo A. Van Ginderachter","doi":"10.1016/j.omtn.2024.102315","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102315","url":null,"abstract":"In recent years, the field of epitranscriptomics has witnessed significant breakthroughs with the identification of more than 150 different chemical modifications in different RNA species. It has become increasingly clear that these chemical modifications play an important role in the regulation of fundamental processes linked to cell fate and development. Further interest was sparked by the ability of the epitranscriptome to regulate pathogenesis. However, despite the involvement of macrophages in a multitude of diseases, a clear knowledge gap exists in the understanding of how RNA modifications regulate the phenotype of these cells. Here, we provide a comprehensive overview of the known roles of macrophage RNA modifications in the context of different diseases.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"10 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.omtn.2024.102301
Derek Sun, William R. Lagor
{"title":"Less is more: Allele-specific removal of dysfunctional RYR1 channel subunits","authors":"Derek Sun, William R. Lagor","doi":"10.1016/j.omtn.2024.102301","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102301","url":null,"abstract":"","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"112 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.omtn.2024.102314
Ella Borgenheimer, Cameron Trueblood, Bryan L. Nguyen, William R. Lagor, Joanna L. Jankowsky
Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that simply replacing the Gaussia luciferase signal peptide with the mouse immunoglobulin heavy chain signal peptide increased release of variant Aβ by ∼5-fold. Sequence modifications within the expressed minigene further increased peptide release by promoting γ-secretase cleavage. Addition of a cytosolic fusion tag compatible with γ-secretase interaction allowed viral transduction to be tracked by immunostaining, independent from the variant Aβ peptide. Collectively these construct modifications increased neuronal production of therapeutic peptide by 10-fold upon intracranial AAV injection of neonatal mice. These findings demonstrate that modest changes in expression vector design can yield substantial gains in AAV efficiency for therapeutic applications.
{"title":"Simple improvements in vector design afford substantial gains in AAV delivery of aggregation-slowing Aβ variants","authors":"Ella Borgenheimer, Cameron Trueblood, Bryan L. Nguyen, William R. Lagor, Joanna L. Jankowsky","doi":"10.1016/j.omtn.2024.102314","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102314","url":null,"abstract":"Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that simply replacing the Gaussia luciferase signal peptide with the mouse immunoglobulin heavy chain signal peptide increased release of variant Aβ by ∼5-fold. Sequence modifications within the expressed minigene further increased peptide release by promoting γ-secretase cleavage. Addition of a cytosolic fusion tag compatible with γ-secretase interaction allowed viral transduction to be tracked by immunostaining, independent from the variant Aβ peptide. Collectively these construct modifications increased neuronal production of therapeutic peptide by 10-fold upon intracranial AAV injection of neonatal mice. These findings demonstrate that modest changes in expression vector design can yield substantial gains in AAV efficiency for therapeutic applications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"22 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1016/j.omtn.2024.102299
Simon C.C. Shiu, Andrew B. Kinghorn, Julian A. Tanner
{"title":"Topical DNA aptamer therapeutics for the skin","authors":"Simon C.C. Shiu, Andrew B. Kinghorn, Julian A. Tanner","doi":"10.1016/j.omtn.2024.102299","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102299","url":null,"abstract":"","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"22 1","pages":"102299"},"PeriodicalIF":8.8,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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