Molecular engineering of short half-life small peptides (VIP, alpha MSH and gamma 3MSH) fused to latency-associated peptide results in improved anti-inflammatory therapeutics

作者：Vessillier Sandrine; Adams Gill; Montero Melendez Trinidad; Jones Rita; Seed Michael; Perretti Mauro; Chernajovsky Yuti^*

来源：Annals of the Rheumatic Diseases, 2012, 71(1): 143-149.

DOI：10.1136/annrheumdis-2011-200100

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 beta 1 through a cleavable matrix metalloproteinase (MMP) linker. This design improves efficacy, overcoming the limitations to their clinical use. %26lt;br%26gt;Methods We generated latent forms of vasoactive intestinal peptide (VIP), alpha-melanocyte-stimulating hormone (MSH) and gamma 3MSH 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. %26lt;br%26gt;Results The recruitment of the polymorphonuclear cells induced by MSU injection into mouse peritoneal cavity was reduced by 35% with gamma 3MSH (1 nmol), whereas administration of a much lower dose of purified latent LAP-MMP-gamma 3MSH (0.03 nmol) attenuated leucocyte influx by 50%. Intramuscular gene delivery of plasmids coding LAP-MMP-VIP and LAP-MMP-alpha MSH 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-alpha MSH. Antibody titres to collagen type II and inflammatory cytokine production were also reduced in these two groups. %26lt;br%26gt;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.

• 出版日期2012-1