VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

Jennifer Bosco, Zhiwei Zhou, Sofie Gabriëls, Mayank Verma, Nan Liu, Brian K. Miller, Sheng Gu, Dianna M. Lundberg, Yan Huang, Eilish Brown, Serene Josiah, Muthuraman Meiyappan, Matthew J. Traylor, Nancy Chen, Atsushi Asakura, Natalie De Jonge, Christophe Blanchetot, Hans de Haard, Heather S. Duffy, Dennis Keefe

Research output: Contribution to journalArticlepeer-review


Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mdx mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6–12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mdx mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy.

Original languageEnglish (US)
Pages (from-to)369-381
Number of pages13
JournalMolecular Therapy - Methods and Clinical Development
StatePublished - Jun 11 2021

Bibliographical note

Funding Information:
This work was conducted in Lexington, MA, USA; Minneapolis, MN, USA; Ashland, OH, USA; Madison, WI, USA; and Zwijnaarde, Belgium. The interpretation of the data was made by the authors independently. The studies were sponsored by Shire Human Genetic Therapies , a Takeda company (Lexington, MA, USA). Medical writing support was provided by Excel Medical Affairs and funded by Shire . Editorial assistance in formatting, proofreading, copyediting, and fact checking also was provided by Excel Medical Affairs. Shire Human Genetic Therapies , a Takeda company, provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

Publisher Copyright:
© 2021


  • Duchenne muscular dystrophy
  • angiogenesis
  • fibrosis
  • monoclonal antibody
  • vascular endothelial growth factor

PubMed: MeSH publication types

  • Journal Article


Dive into the research topics of 'VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy'. Together they form a unique fingerprint.

Cite this