Development of functional aptamers as therapeutic agents

Our lab has been developing functional DNA aptamers - namely DNA oligonucleotides that exhibit antagonistic or agonistic effects on cellular signalling pathways and cellular processes. Current efforts have focused on the development of both agonistic (CD200R1) and antagonistic (PD-1) (Figure 2) aptamers to immune checkpoint targets with a view to developing therapeutic oligonucleotides aimed at dampening inflammatory responses or enhancing anti-tumor responses.

What is an Aptamer ?

“Aptamers” are single stranded nucleic acids (RNA or ssDNA) which bind to molecular targets of interest with high affinity and high specificity. Such sequences, which are generally 15-90 bases in length, are derived to a selected target through an iterative in vitro selection process known as SELEX (Figure 1). These aptamers bind to target molecules such as proteins with comparable affinity (KD) to monoclonal antibodies. In contrast to monoclonal antibodies however, aptamers have distinct advantages, including 1) low immunogenicity, 2) inexpensive chemical synthesis, and 3) long shelf life. Furthermore, chemical moieties can be readily conjugated to defined sites on aptamers, enabling the use of aptamers in a multitude of applications including drug targeting, imaging, biosensors, bioanalysis, immunohistochemistry, and in vivo drug targeting.

Figure 1. SELEX: Systematic Evolution of Ligands by Exponential Enrichment is used to evolve aptamers towards targets of therapeutic relevance.

MP7 docked against mouse PD1-cropped-for-website.png

Figure 2. Predicted molecular docking pose of MP7 aptamer binding to mouse PD-1 monomeric unit using Biovia Discover Studio 2016.

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Selected publications from our group:

1. Orava EW, Abdul-Wahid A, Huang EH, Mallick AI, Gariépy J. (2013) Blocking the attachment of cancer cells in vivo with DNA aptamers displaying anti-adhesive properties against the carcinoembryonic antigen. Mol Oncol7(4):799-811 

2. Orava EW, Jarvik N, Shek J, Sidhu SS, Garipéy J. (2013) A short DNA aptamer that recognizes TFN-α and blocks its activity in vitro. ACS Chem Biol. 8(1):170-178

3. Prodeus A, Abdul-Wahid A, Fischer NW, Huang EH, Cydzik M, Gariépy J. (2015) Targeting the PD-1/PD-L1 immune evasion axis with DNA aptamers as a novel therapeutic strategy for the treatment of disseminated cancers. Mol Ther Nucleic Acids. 4:e237

 

4. Prodeus A, Cydzik M, Abdul-Wahid A, Huang EH, Khatri I, Gorczynski R, Gariépy J. (2014) Agonistic CD200R1 DNA aptamers are potent immunosuppressants that prolong allogeneic skin graft survival. Mol Ther Nucleic Acids. 3:e190 

5. Prodeus A*, Sparkes A*, Fischer N, Cydzik M, Huang E, Khatri I, Young A, Woo L, Chow CW, Gorczynski R, and Gariépy J (2018) [* Co-first authorship] A synthetic cross-species CD200R1 agonist suppresses inflammatory immune responses in vivo. Mol Ther Nucleic Acids. 12:350–358

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Last updated on September-12-2022