In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy

Sourav R. Choudhury, Zachary Fitzpatrick, Anne F. Harris, Stacy A. Maitland, Jennifer S. Ferreira, Yuanfan Zhang, Shan Ma, Rohit B. Sharma, Heather L. Gray-Edwards, Jacob A. Johnson, Aime K. Johnson, Laura C. Alonso, Claudio Punzo, Kathryn R. Wagner, Casey A. Maguire, Robert M. Kotin, Douglas R. Martin, Miguel Sena-Esteves

Research output: Contribution to journalArticle

Abstract

Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, β-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.Molecular Therapy (2016); doi:10.1038/mt.2016.84.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - Jun 7 2016

Fingerprint

Capsid
Genetic Therapy
Central Nervous System
Muscles
Genes
Pulmonary Alveoli
Nervous System Diseases
Pancreas
Spinal Cord
Cats
Lung
Antibodies
Brain
Serum

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Choudhury, S. R., Fitzpatrick, Z., Harris, A. F., Maitland, S. A., Ferreira, J. S., Zhang, Y., ... Sena-Esteves, M. (2016). In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy. Molecular Therapy. DOI: 10.1038/mt.2016.84

In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy. / Choudhury, Sourav R.; Fitzpatrick, Zachary; Harris, Anne F.; Maitland, Stacy A.; Ferreira, Jennifer S.; Zhang, Yuanfan; Ma, Shan; Sharma, Rohit B.; Gray-Edwards, Heather L.; Johnson, Jacob A.; Johnson, Aime K.; Alonso, Laura C.; Punzo, Claudio; Wagner, Kathryn R.; Maguire, Casey A.; Kotin, Robert M.; Martin, Douglas R.; Sena-Esteves, Miguel.

In: Molecular Therapy, 07.06.2016.

Research output: Contribution to journalArticle

Choudhury, SR, Fitzpatrick, Z, Harris, AF, Maitland, SA, Ferreira, JS, Zhang, Y, Ma, S, Sharma, RB, Gray-Edwards, HL, Johnson, JA, Johnson, AK, Alonso, LC, Punzo, C, Wagner, KR, Maguire, CA, Kotin, RM, Martin, DR & Sena-Esteves, M 2016, 'In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy' Molecular Therapy. DOI: 10.1038/mt.2016.84
Choudhury SR, Fitzpatrick Z, Harris AF, Maitland SA, Ferreira JS, Zhang Y et al. In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy. Molecular Therapy. 2016 Jun 7. Available from, DOI: 10.1038/mt.2016.84

Choudhury, Sourav R.; Fitzpatrick, Zachary; Harris, Anne F.; Maitland, Stacy A.; Ferreira, Jennifer S.; Zhang, Yuanfan; Ma, Shan; Sharma, Rohit B.; Gray-Edwards, Heather L.; Johnson, Jacob A.; Johnson, Aime K.; Alonso, Laura C.; Punzo, Claudio; Wagner, Kathryn R.; Maguire, Casey A.; Kotin, Robert M.; Martin, Douglas R.; Sena-Esteves, Miguel / In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy.

In: Molecular Therapy, 07.06.2016.

Research output: Contribution to journalArticle

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abstract = "Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, β-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.Molecular Therapy (2016); doi:10.1038/mt.2016.84.",
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