CoChat
Sign Up
Cited by 620Virus-based gene therapy researchRNA Interference and Gene DeliveryNeurogenetic and Muscular Disorders Research

Systemic delivery of genes to striated muscles using adeno-associated viral vectors

Open access
Gregorevic, Paul, Blankinship, Michael J, Allen, James M, Crawford, Robert W, Meuse, Leonard, Miller, Daniel G, Russell, David W, Chamberlain, Jeffrey S·2004·Nature Medicine
DOI 10.1038/nm1085PMC PMC1365046
Open this paper in CoChat — free account

Abstract

A major obstacle limiting gene therapy for diseases of the heart and skeletal muscles is an inability to deliver genes systemically to muscles of an adult organism. Systemic gene transfer to striated muscles is hampered by the vascular endothelium, which represents a barrier to distribution of vectors via the circulation. Here we show the first evidence of widespread transduction of both cardiac and skeletal muscles in an adult mammal, after a single intravenous administration of recombinant adeno-associated virus pseudotype 6 vectors. The inclusion of vascular endothelium growth factor/vascular permeability factor, to achieve acute permeabilization of the peripheral microvasculature, enhanced tissue transduction at lower vector doses. This technique enabled widespread muscle-specific expression of a functional micro-dystrophin in the skeletal muscles of dystrophin-deficient mdx mice, which model Duchenne muscular dystrophy. We propose that these methods may be applicable for systemic delivery of a wide variety of genes to the striated muscles of adult mammals.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nm1085

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Early research conducted in murine and canine models of DMD paved the way for clinical investigation.

    “Early research conducted in murine and canine models of DMD [119-121] paved the way for clinical investigation.”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [120]

    The Results describe gene-delivery experiments in mdx mice, a murine model of DMD, and the Discussion identifies potential clinical applications. Our copy does not describe research in a canine DMD model or establish that this work paved the way for clinical investigation; its mention of canine subjects concerns other AAV research. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 32

  1. [1]Hoshijima M, et al. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med. 2002;8:864–871. doi: 10.1038/nm739. [DOI] [PubMed] [Google Scholar] · DOI
  2. [3]Harper SQ, et al. Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Nat Med. 2002;8:253–261. doi: 10.1038/nm0302-253. [DOI] [PubMed] [Google Scholar] · DOI
  3. [4]Greelish JP, et al. Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector. Nat Med. 1999;5:439–443. doi: 10.1038/7439. [DOI] [PubMed] [Google Scholar] · DOI
  4. [5]Bridges CR, et al. Global cardiac-specific transgene expression using cardiopulmonary bypass with cardiac isolation. Ann Thorac Surg. 2002;73:1939–1946. doi: 10.1016/s0003-4975(02)03509-9. [DOI] [PubMed] [Google Scholar] · DOI
  5. [6]Huard J, et al. The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants. Gene Ther. 1995;2:107–115. [PubMed] [Google Scholar]
  6. [7]Cho WK, et al. Modulation of Starling forces and muscle fiber maturity permits adenovirus-mediated gene transfer to adult dystrophic (mdx) mice by the intravascular route. Hum Gene Ther. 2000;11:701–714. doi: 10.1089/10430340050015608. [DOI] [PubMed] [Google Scholar] · DOI
  7. [8]Zhang G, Budker V, Williams P, Hanson K, Wolff JA. Surgical procedures for intravascular delivery of plasmid DNA to organs. Methods Enzymol. 2002;346:125–133. doi: 10.1016/s0076-6879(02)46052-1. [DOI] [PubMed] [Google Scholar] · DOI
  8. [9]Dellorusso C, et al. Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin. Proc Natl Acad Sci USA. 2002;99:12979–12984. doi: 10.1073/pnas.202300099. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  9. [10]Watchko J, et al. Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther. 2002;13:1451–1460. doi: 10.1089/10430340260185085. [DOI] [PubMed] [Google Scholar] · DOI
  10. [11]Halbert CL, Rutledge EA, Allen JM, Russell DW, Miller AD. Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol. 2000;74:1524–1532. doi: 10.1128/jvi.74.3.1524-1532.2000. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  11. [12]Scott JM, et al. Viral vectors for gene transfer of micro-, mini-, or full-length dystrophin. Neuromuscul Disord. 2002;12:S23–S29. doi: 10.1016/s0960-8966(02)00078-0. [DOI] [PubMed] [Google Scholar] · DOI
  12. [13]Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995;108:2369–2379. doi: 10.1242/jcs.108.6.2369. [DOI] [PubMed] [Google Scholar] · DOI
  13. [14]Senger DR, Perruzzi CA, Feder J, Dvorak HF. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986;46:5629–5632. [PubMed] [Google Scholar]
  14. [15]Hauser MA, et al. Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors. Mol Ther. 2000;2:16–25. doi: 10.1006/mthe.2000.0089. [DOI] [PubMed] [Google Scholar] · DOI
  15. [16]Hartigan-O’Connor D, Kirk CJ, Crawford R, Mule JJ, Chamberlain JS. Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol Ther. 2001;4:525–533. doi: 10.1006/mthe.2001.0496. [DOI] [PubMed] [Google Scholar] · DOI
  16. [17]Grimm D, et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood. 2003;102:2412–2419. doi: 10.1182/blood-2003-02-0495. [DOI] [PubMed] [Google Scholar] · DOI
  17. [18]Yuasa K, et al. Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product. Gene Ther. 2002;9:1576–1588. doi: 10.1038/sj.gt.3301829. [DOI] [PubMed] [Google Scholar] · DOI
  18. [19]Pinson KI, Dunbar L, Samuelson L, Gumucio DL. Targeted disruption of the mouse villin gene does not impair the morphogenesis of microvilli. Dev Dyn. 1998;211:109–121. doi: 10.1002/(SICI)1097-0177(199801)211:1<109::AID-AJA10>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar] · DOI
  19. [20]Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci USA. 1993;90:3710–3714. doi: 10.1073/pnas.90.8.3710. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  20. [21]Gregorevic P, Chamberlain JS. Gene therapy for muscular dystrophy - a review of promising progress. Expert Opin Biol Ther. 2003;3:803–814. doi: 10.1517/14712598.3.5.803. [DOI] [PubMed] [Google Scholar] · DOI
  21. [22]Sakamoto M, et al. Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene. Biochem Biophys Res Commun. 2002;293:1265–1272. doi: 10.1016/S0006-291X(02)00362-5. [DOI] [PubMed] [Google Scholar] · DOI
  22. [23]Ahmad A, Brinson M, Hodges BL, Chamberlain JS, Amalfitano A. Mdx mice inducibly expressing dystrophin provide insights into the potential of gene therapy for Duchenne muscular dystrophy. Hum Mol Genet. 2000;9:2507–2515. doi: 10.1093/hmg/9.17.2507. [DOI] [PubMed] [Google Scholar] · DOI
  23. [24]Phelps SF, et al. Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice. Hum Mol Genet. 1995;4:1251–1258. doi: 10.1093/hmg/4.8.1251. [DOI] [PubMed] [Google Scholar] · DOI
  24. [25]Arruda VR, et al. Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther. 2001;4:586–592. doi: 10.1006/mthe.2001.0491. [DOI] [PubMed] [Google Scholar] · DOI
  25. [26]Herzog RW, et al. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy. Hum Gene Ther. 2002;13:1281–1291. doi: 10.1089/104303402760128513. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  26. [27]Manno CS, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003;101:2963–2972. doi: 10.1182/blood-2002-10-3296. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  27. [28]Eppler SM, et al. A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther. 2002;72:20–32. doi: 10.1067/mcp.2002.126179. [DOI] [PubMed] [Google Scholar] · DOI
  28. [29]Herzog RW, et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med. 1999;5:56–63. doi: 10.1038/4743. [DOI] [PubMed] [Google Scholar] · DOI
  29. [30]Rutledge EA, Halbert CL, Russell DW. Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol. 1998;72:309–319. doi: 10.1128/jvi.72.1.309-319.1998. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  30. [31]Grimm D, Kern A, Rittner K, Kleinschmidt JA. Novel tools for production and purification of recombinant adeno-associated virus vectors. Hum Gene Ther. 1998;9:2745–2760. doi: 10.1089/hum.1998.9.18-2745. [DOI] [PubMed] [Google Scholar] · DOI
  31. [32]Halbert CL, Allen JM, Miller AD. Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors. J Virol. 2001;75:6615–6624. doi: 10.1128/JVI.75.14.6615-6624.2001. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. [33]Rafael JA, et al. Forced expression of dystrophin deletion constructs reveals structure-function correlations. J Cell Biol. 1996;134:93–102. doi: 10.1083/jcb.134.1.93. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Gregorevic, P., Blankinship, M. J., Allen, J. M., Crawford, R. W., Meuse, L., Miller, D. G., Russell, D. W., & Chamberlain, J. S.
Affiliations
University of Washington (US)
Corresponding author
Chamberlain, Jeffrey S
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2004-07-25
Volume
10
Issue
8
Pages
828-834
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm1085
PMC
PMC1365046
OpenAlex
W1966493859
Cited by
620
References
1
Citations by year
2026: 12 · 2025: 15 · 2024: 8 · 2023: 15 · 2022: 18 · 2021: 20 · 2020: 15 · 2019: 22 · 2018: 20 · 2017: 22 · 2016: 25 · 2015: 36 · 2014: 26 · 2013: 21 · 2012: 36
FWCI
23.14
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (P01AG015434)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K08DK062100, R01DK055759)
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
adeno-associated virus vectors, systemic gene delivery, striated muscle, vascular endothelium, vascular endothelial growth factor, myocardium, skeletal muscle, dystrophin, Duchenne muscular dystrophy, mdx mice, intravenous administration, vector dose
MeSH terms
Animals, Capillary Permeability, Chromatography, Affinity, Disease Models, Animal, Endothelium, Genetic Vectors, Injections, Intravenous, Mice, Inbred C57BL, Microscopy, Fluorescence, Muscle Contraction, Genetic Therapy, Dystrophin, DNA Primers, Parvovirus, Muscle, Skeletal, Muscular Dystrophy, Duchenne, Vascular Endothelial Growth Factor A, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review