Optimized AAV capsids for basal ganglia diseases show robust potency and distribution
Abstract Huntington’s disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Here, we found that low dose, low volume delivery of unbiased AAV li...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60000-3 |
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| author | D. E. Leib Y. H. Chen L. Tecedor P. T. Ranum M. S. Keiser B. C. Lewandowski E. M. Carrell S. Arora I. Huerta-Ocampo D. Lai C. M. Fluta C. Cheng X. Liu B. L. Davidson |
| author_facet | D. E. Leib Y. H. Chen L. Tecedor P. T. Ranum M. S. Keiser B. C. Lewandowski E. M. Carrell S. Arora I. Huerta-Ocampo D. Lai C. M. Fluta C. Cheng X. Liu B. L. Davidson |
| author_sort | D. E. Leib |
| collection | DOAJ |
| description | Abstract Huntington’s disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Here, we found that low dose, low volume delivery of unbiased AAV libraries into the globus pallidus allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use. |
| format | Article |
| id | doaj-art-69cfa8aaea00462aaa0dafe834a5a93b |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-69cfa8aaea00462aaa0dafe834a5a93b2025-08-20T02:34:04ZengNature PortfolioNature Communications2041-17232025-05-0116111410.1038/s41467-025-60000-3Optimized AAV capsids for basal ganglia diseases show robust potency and distributionD. E. Leib0Y. H. Chen1L. Tecedor2P. T. Ranum3M. S. Keiser4B. C. Lewandowski5E. M. Carrell6S. Arora7I. Huerta-Ocampo8D. Lai9C. M. Fluta10C. Cheng11X. Liu12B. L. Davidson13Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaDepartment of Neurological Surgery, Neurotech Institute, The Ohio State UniversityRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaLatus BioRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaRaymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of PhiladelphiaAbstract Huntington’s disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Here, we found that low dose, low volume delivery of unbiased AAV libraries into the globus pallidus allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use.https://doi.org/10.1038/s41467-025-60000-3 |
| spellingShingle | D. E. Leib Y. H. Chen L. Tecedor P. T. Ranum M. S. Keiser B. C. Lewandowski E. M. Carrell S. Arora I. Huerta-Ocampo D. Lai C. M. Fluta C. Cheng X. Liu B. L. Davidson Optimized AAV capsids for basal ganglia diseases show robust potency and distribution Nature Communications |
| title | Optimized AAV capsids for basal ganglia diseases show robust potency and distribution |
| title_full | Optimized AAV capsids for basal ganglia diseases show robust potency and distribution |
| title_fullStr | Optimized AAV capsids for basal ganglia diseases show robust potency and distribution |
| title_full_unstemmed | Optimized AAV capsids for basal ganglia diseases show robust potency and distribution |
| title_short | Optimized AAV capsids for basal ganglia diseases show robust potency and distribution |
| title_sort | optimized aav capsids for basal ganglia diseases show robust potency and distribution |
| url | https://doi.org/10.1038/s41467-025-60000-3 |
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