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Cited by 56Virus-based gene therapy researchRNA Interference and Gene DeliveryNeurogenetic and Muscular Disorders Research

Adeno-associated virus serotype 9 efficiently targets ischemic skeletal muscle following systemic delivery

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Katwal, A B, Konkalmatt, P R, Piras, B A, Hazarika, S, Li, S S, John Lye, R, Sanders, J M, Ferrante, E A +3 more·2013·Gene Therapy
DOI 10.1038/gt.2013.16PMC PMC3758463
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Abstract

Targeting therapeutic gene expression to the skeletal muscle following intravenous (IV) administration is an attractive strategy for treating peripheral arterial disease (PAD), except that vector access to the ischemic limb could be a limiting factor. As adeno-associated virus serotype 9 (AAV-9) transduces skeletal muscle at high efficiency following systemic delivery, we employed AAV-9 vectors bearing luciferase or enhanced green fluorescent protein (eGFP) reporter genes to test the hypothesis that increased desialylation of cell-surface glycans secondary to hindlimb ischemia (HLI) might help offset the reduction in tissue perfusion that occurs in mouse models of PAD. The utility of the creatine kinase-based (CK6) promoter for restricting gene expression to the skeletal muscle was also examined by comparing it with the cytomegalovirus (CMV) promoter after systemic administration following surgically induced HLI. Despite reduced blood flow to the ischemic limbs, CK6 promoter-driven luciferase activities in the ischemic gastrocnemius (GA) muscles were ∼34-, ∼28- and ∼150-fold higher than in the fully perfused contralateral GA, heart and liver, respectively, 10 days after IV administration. Furthermore, luciferase activity from the CK6 promoter in the ischemic GA muscles was ∼twofold higher than with CMV, while in the liver CK6-driven activity was ∼42-fold lower than with CMV, demonstrating that the specificity of ischemic skeletal muscle transduction can be further improved with the muscle-specific promoters. Studies with Evans blue dye and fluorescently labeled lectins revealed that vascular permeability and desialylation of the cell-surface glycans were increased in the ischemic hindlimbs. Furthermore, AAV9/CK6/Luc vector genome copy numbers were ∼sixfold higher in the ischemic muscle compared with the non-ischemic muscle in the HLI model, whereas this trend was reversed when the same genome was packaged in the AAV-1 capsid (which binds sialylated, as opposed to desialylated glycans), further underscoring the importance of desialylation in the ischemic enhancement of transduction displayed by AAV-9. Taken together, these findings suggest two complementary mechanisms contributing to the preferential transduction of ischemic muscle by AAV-9: increased vascular permeability and desialylation. In conclusion, ischemic muscle is preferentially targeted following systemic administration of AAV-9 in a mouse model of HLI. Unmasking of the primary AAV-9 receptor as a result of ischemia may contribute importantly to this effect.

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  • A revised paradigm currently considers the use of muscle-specific promoters to prevent leaky expression, as well as systemic vector delivery for broader biodistribution via AAV9 and/or AAVrh74, which efficiently target both striated muscle and the CNS.

    “To overcome these limitations, a revised paradigm currently considers the use of muscle-specific promoters to prevent leaky expression, as well as systemic vector delivery for broader biodistribution via AAV9 and/or AAVrh74, which efficiently target both striated muscle and the CNS [123-125].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [123]

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Cited by

Sorted by citations

Authors
Katwal, A. B., Konkalmatt, P. R., Piras, B. A., Hazarika, S., Li, S. S., John Lye, R., Sanders, J. M., Ferrante, E. A., Yan, Z., Annex, B. H., & French, B. A.
Affiliations
University of Virginia (US)
Corresponding author
French, B A
ORCID
Venue
Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2013-03-28
Volume
20
Issue
9
Pages
930-938
ISSN
  • 0969-7128 (ISSN-L)
  • 1476-5462
DOI
10.1038/gt.2013.16
PMC
PMC3758463
OpenAlex
W2030524071
Cited by
56
References
3
Citations by year
2026: 3 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 2 · 2014: 8 · 2013: 3
FWCI
3.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Gene Therapy (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5r01hl058582-07)
  • National Heart, Lung, and Blood Institute (R01-HL-058582, T32 HL073555, R01HL101200, T32HL007284)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050429)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Keywords
AAV9, hindlimb ischemia, peripheral arterial disease, desialylation, cell surface glycans, vascular permeability, muscle-specific promoter, AAV capsid, tissue perfusion
MeSH terms
Dependovirus, Animals, Genetic Vectors, Hindlimb, Humans, Ischemia, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Polysaccharides, Promoter Regions, Genetic, Transduction, Genetic, Genetic Therapy, Genes, Reporter, Muscle, Skeletal, Mice, Peripheral Arterial Disease

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