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Molecular engineering of short half-life small peptides (VIP, αMSH and γ3MSH) fused to latency-associated peptide results in improved anti-inflammatory therapeutics
  1. Sandrine Vessillier1,
  2. Gill Adams1,
  3. Trinidad Montero-Melendez2,
  4. Rita Jones3,
  5. Michael Seed3,
  6. Mauro Perretti2,
  7. Yuti Chernajovsky1
  1. 1Bone and Joint Research Unit, William Harvey Research Institute, London, UK
  2. 2Biochemical Pharmacology, William Harvey Research Institute, London, UK
  3. 3Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK
  1. Correspondence to Professor Yuti Chernajovsky, Bone and Joint Research Unit, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK; y.chernajovsky{at}qmul.ac.uk

Abstract

Objective To facilitate the targeting to inflammation sites of small anti-inflammatory peptides, with short half-lives, by fusion with the latency-associated peptide (LAP) of transforming growth factor β1 through a cleavable matrix metalloproteinase (MMP) linker. This design improves efficacy, overcoming the limitations to their clinical use.

Methods We generated latent forms of vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (MSH) and γ3MSH by fusion to LAP through an MMP cleavage site using recombinant DNA technology. The biological activities of these latent therapeutics were studied in vivo using monosodium urate (MSU)-induced peritonitis and collagen-induced arthritis (CIA) models. We assessed gene therapy and purified protein therapy.

Results The recruitment of the polymorphonuclear cells induced by MSU injection into mouse peritoneal cavity was reduced by 35% with γ3MSH (1 nmol), whereas administration of a much lower dose of purified latent LAP–MMP–γ3MSH (0.03 nmol) attenuated leucocyte influx by 50%. Intramuscular gene delivery of plasmids coding LAP–MMP–VIP and LAP–MMP–αMSH at disease onset reduced the development of CIA compared with LAP–MMP, which does not contain any therapeutic moiety. Histological analysis confirmed a significantly lower degree of inflammation, bone and cartilage erosion in groups treated with LAP–MMP–VIP or LAP–MMP–αMSH. Antibody titres to collagen type II and inflammatory cytokine production were also reduced in these two groups.

Conclusion Incorporation of small anti-inflammatory peptides within the LAP shell and delivered as recombinant protein or through gene therapy can control inflammatory and arthritic disease. This platform delivery can be developed to control human arthritides and other autoimmune diseases.

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Footnotes

  • Funding This study was funded by the Wellcome Trust, university translational award (073271) and Arthritis Research UK. MS is funded by a fellowship from the William Harvey Research Foundation.

  • Competing interests YC is founder and director of Stealthyx Therapeutics, which develops the latent cytokine platform delivery technology.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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