AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

doi:10.1038/s41593-021-00969-4

. 2022 Jan;25(1):106-115.

doi: 10.1038/s41593-021-00969-4. Epub 2021 Dec 9.

AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

David Goertsen^#¹, Nicholas C Flytzanis^#¹, Nick Goeden^#¹, Miguel R Chuapoco¹, Alexander Cummins², Yijing Chen³, Yingying Fan³, Qiangge Zhang^{4

5}, Jitendra Sharma^{4

6

7

8}, Yangyang Duan⁹, Liping Wang³, Guoping Feng^{4

5}, Yu Chen^{3

10}, Nancy Y Ip^{9

11

10}, James Pickel², Viviana Gradinaru¹²

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
² National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
³ Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
⁴ McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Tan & Yang Center for Autism Research, McGovern Institute of Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
¹⁰ Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China.
¹² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. viviana@caltech.edu.

^# Contributed equally.

PMID: 34887588
DOI: 10.1038/s41593-021-00969-4

AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

David Goertsen et al. Nat Neurosci. 2022 Jan.

. 2022 Jan;25(1):106-115.

doi: 10.1038/s41593-021-00969-4. Epub 2021 Dec 9.

Authors

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
² National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
³ Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
⁴ McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Tan & Yang Center for Autism Research, McGovern Institute of Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
¹⁰ Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China.
¹² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. viviana@caltech.edu.

^# Contributed equally.

PMID: 34887588
DOI: 10.1038/s41593-021-00969-4

Abstract

Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies rely upon expressing a transgene in affected cells while minimizing off-target expression. Here we show organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery, which we achieved by employing a Cre-transgenic-based screening platform and sequential engineering of AAV-PHP.eB between the surface-exposed AA452 and AA460 of VP3. From this selection, we identified capsid variants that were enriched in the brain and targeted away from the liver in C57BL/6J mice. This tropism extends to marmoset (Callithrix jacchus), enabling robust, non-invasive gene delivery to the marmoset brain after intravenous administration. Notably, the capsids identified result in distinct transgene expression profiles within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates enables new avenues for basic research and therapeutic possibilities unattainable with naturally occurring serotypes.

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Comment in

Targeted Gene Therapy to Treat Disorders of the Central Nervous System.
Sasikumar S, Ingelsson M. Sasikumar S, et al. Mov Disord. 2022 May;37(5):892. doi: 10.1002/mds.29017. Epub 2022 Apr 1. Mov Disord. 2022. PMID: 35362633 No abstract available.

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References

1. Naso, M. F., Tomkowicz, B., Perry, W. L. & Strohl, W. R. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 31, 317–334 (2017). - PubMed - PMC - DOI
1. Gaudet, D., Méthot, J. & Kastelein, J. Gene therapy for lipoprotein lipase deficiency. Curr. Opin. Lipidol. 23, 310–320 (2012). - PubMed - DOI
1. Al-Zaidy, S. A. & Mendell, J. R. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr. Neurol. 100, 3–11 (2019). - PubMed - DOI
1. Ameri, H. Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation. J. Curr. Ophthalmol. 30, 1–2 (2018). - PubMed - PMC - DOI
1. Evens, H., Chuah, M. K. & VandenDriessche, T. Haemophilia gene therapy: from trailblazer to gamechanger. Haemophilia 24, 50–59 (2018). - PubMed - DOI

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[1] Naso, M. F., Tomkowicz, B., Perry, W. L. & Strohl, W. R. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 31, 317–334 (2017). - PubMed - PMC - DOI

[2] Naso, M. F., Tomkowicz, B., Perry, W. L. & Strohl, W. R. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 31, 317–334 (2017). - PubMed - PMC - DOI

[3] Gaudet, D., Méthot, J. & Kastelein, J. Gene therapy for lipoprotein lipase deficiency. Curr. Opin. Lipidol. 23, 310–320 (2012). - PubMed - DOI

[4] Gaudet, D., Méthot, J. & Kastelein, J. Gene therapy for lipoprotein lipase deficiency. Curr. Opin. Lipidol. 23, 310–320 (2012). - PubMed - DOI

[5] Al-Zaidy, S. A. & Mendell, J. R. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr. Neurol. 100, 3–11 (2019). - PubMed - DOI

[6] Al-Zaidy, S. A. & Mendell, J. R. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr. Neurol. 100, 3–11 (2019). - PubMed - DOI

[7] Ameri, H. Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation. J. Curr. Ophthalmol. 30, 1–2 (2018). - PubMed - PMC - DOI

[8] Ameri, H. Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation. J. Curr. Ophthalmol. 30, 1–2 (2018). - PubMed - PMC - DOI

[9] Evens, H., Chuah, M. K. & VandenDriessche, T. Haemophilia gene therapy: from trailblazer to gamechanger. Haemophilia 24, 50–59 (2018). - PubMed - DOI

[10] Evens, H., Chuah, M. K. & VandenDriessche, T. Haemophilia gene therapy: from trailblazer to gamechanger. Haemophilia 24, 50–59 (2018). - PubMed - DOI

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AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

Affiliations

AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

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