A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application

Abstract

Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.

Cyclic Peptide-Based Biologics Regulating HGF-MET

“…Based on the concept that growth factor receptor activation depends on receptor dimerization, HGF-mimetic molecules, were discovered by different approaches [27][28][29][30][31][32][33][34][35][36]. These approaches include the use of: monoclonal antibodies based on the bivalent characteristic of antibodies [27][28][29][30][31]; the engineered protein eNK1, created by the disulfide-linked NK1 (N-terminal and the first kringle) domains of HGF [32,33]; the semi-synthetic engineered K1 domain, designed to be multimer by biotin-avidin interaction [34]; and DNA aptamer [35,36] (Figure 10). The MET-agonist monoclonal antibody protects cardiac myocytes from cell death induced by oxidative stress or hypoxia [27][28][29].…”

“…The most potent DNA aptamer is composed solely of unmodified 100-mer single stranded DNA, and it activates MET at EC50 value of 1-5 nM. In a mouse model of fulminant hepatitis, the intravenous administration of a MET-agonistic DNA aptamer increased the MET activation and suppressed the cell death of hepatocytes in the liver [36]. MET agonists created by different approaches are expected to be therapeutic molecules.…”

Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent minimal MET receptor agonist

“…Several MET agonists have been developed over the years, most notably Magic-F1 (56), eNK1 (57), agonistic monoclonal antibodies (58, 59), a group of synthetic cyclic peptides (60) and recently an aptamer (61). Most relevant to our study are Magic-F1 and eNK1 as they are both based on dimers of HGF/SF domains.…”

HGF and MET: From Brain Development to Neurological Disorders

“…Molecules capable of inducing MET receptor dimerization and activation were sought. These MET agonists include anti-MET monoclonal antibodies based on the bivalent characteristic of antibodies ( Prat et al, 1998 ; Pietronave et al, 2010 ; Gallo et al, 2014a ; Yuan et al, 2019 ), the engineered protein eNK1, created by the disulfide-linked NK1 (N-terminal and the K1 first kringle) domains of HGF ( Jones et al, 2011 ; Liu et al, 2014 ), a novel dimeric form of the K1 domain, designated K1K1 ( Vallarola et al, 2020 ), the semi-synthetic engineered K1 domain, designed to be multimer by biotin-avidin interaction ( Simonneau et al, 2015 ), a MET-agonistic DNA aptamer ( Ueki et al, 2016 , 2020 ), and MET-agonistic synthetic macrocyclic peptides ( Sato et al, 2020 ). All these MET agonists created by different strategies are expected to augment the therapeutic armamentarium for brain repair and neurological and neurodegenerative diseases.…”