Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders
Adeno-associated virus (AAV)-based gene therapy is a clinical stage therapeutic modality for neurological disorders. A common genetic defect in myriad monogenic neurological disorders is nonsense mutations that account for about 11% of all human pathogenic mutations. Stop codon readthrough by suppre...
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Elsevier
2024-07-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747924000771 |
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| author | Jiaming Wang Guangping Gao Dan Wang |
| author_facet | Jiaming Wang Guangping Gao Dan Wang |
| author_sort | Jiaming Wang |
| collection | DOAJ |
| description | Adeno-associated virus (AAV)-based gene therapy is a clinical stage therapeutic modality for neurological disorders. A common genetic defect in myriad monogenic neurological disorders is nonsense mutations that account for about 11% of all human pathogenic mutations. Stop codon readthrough by suppressor transfer RNA (sup-tRNA) has long been sought as a potential gene therapy approach to target nonsense mutations, but hindered by inefficient in vivo delivery. The rapid advances in AAV delivery technology have not only powered gene therapy development but also enabled in vivo preclinical assessment of a range of nucleic acid therapeutics, such as sup-tRNA. Compared with conventional AAV gene therapy that delivers a transgene to produce therapeutic proteins, AAV-delivered sup-tRNA has several advantages, such as small gene sizes and operating within the endogenous gene expression regulation, which are important considerations for treating some neurological disorders. This review will first examine sup-tRNA designs and delivery by AAV vectors. We will then analyze how AAV-delivered sup-tRNA can potentially address some neurological disorders that are challenging to conventional gene therapy, followed by discussing available mouse models of neurological diseases for in vivo preclinical testing. Potential challenges for AAV-delivered sup-tRNA to achieve therapeutic efficacy and safety will also be discussed. |
| format | Article |
| id | doaj-art-df387ac4c6094baebea12d928cbd4626 |
| institution | OA Journals |
| issn | 1878-7479 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-df387ac4c6094baebea12d928cbd46262025-08-20T01:54:30ZengElsevierNeurotherapeutics1878-74792024-07-01214e0039110.1016/j.neurot.2024.e00391Developing AAV-delivered nonsense suppressor tRNAs for neurological disordersJiaming Wang0Guangping Gao1Dan Wang2Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USAHorae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding authors.Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding authors.Adeno-associated virus (AAV)-based gene therapy is a clinical stage therapeutic modality for neurological disorders. A common genetic defect in myriad monogenic neurological disorders is nonsense mutations that account for about 11% of all human pathogenic mutations. Stop codon readthrough by suppressor transfer RNA (sup-tRNA) has long been sought as a potential gene therapy approach to target nonsense mutations, but hindered by inefficient in vivo delivery. The rapid advances in AAV delivery technology have not only powered gene therapy development but also enabled in vivo preclinical assessment of a range of nucleic acid therapeutics, such as sup-tRNA. Compared with conventional AAV gene therapy that delivers a transgene to produce therapeutic proteins, AAV-delivered sup-tRNA has several advantages, such as small gene sizes and operating within the endogenous gene expression regulation, which are important considerations for treating some neurological disorders. This review will first examine sup-tRNA designs and delivery by AAV vectors. We will then analyze how AAV-delivered sup-tRNA can potentially address some neurological disorders that are challenging to conventional gene therapy, followed by discussing available mouse models of neurological diseases for in vivo preclinical testing. Potential challenges for AAV-delivered sup-tRNA to achieve therapeutic efficacy and safety will also be discussed.http://www.sciencedirect.com/science/article/pii/S1878747924000771AAVNonsense mutationNeurological disorderPremature termination codonSuppressor tRNA |
| spellingShingle | Jiaming Wang Guangping Gao Dan Wang Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders Neurotherapeutics AAV Nonsense mutation Neurological disorder Premature termination codon Suppressor tRNA |
| title | Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders |
| title_full | Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders |
| title_fullStr | Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders |
| title_full_unstemmed | Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders |
| title_short | Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders |
| title_sort | developing aav delivered nonsense suppressor trnas for neurological disorders |
| topic | AAV Nonsense mutation Neurological disorder Premature termination codon Suppressor tRNA |
| url | http://www.sciencedirect.com/science/article/pii/S1878747924000771 |
| work_keys_str_mv | AT jiamingwang developingaavdeliverednonsensesuppressortrnasforneurologicaldisorders AT guangpinggao developingaavdeliverednonsensesuppressortrnasforneurologicaldisorders AT danwang developingaavdeliverednonsensesuppressortrnasforneurologicaldisorders |