title: RNA aptamer-based functional ligands of the neurotrophin receptor, TrkB.
abstract: Many cell surface signaling receptors, such as the neurotrophin receptor, TrkB, have emerged as potential therapeutic targets for diverse diseases. Reduced activation of TrkB in particular is thought to contribute to neurodegenerative diseases. Unfortunately, development of therapeutic reagents that selectively activate particular cell surface receptors such as TrkB has proven challenging. Like many cell surface signaling receptors, TrkB is internalized upon activation; in this proof-of-concept study, we exploited this fact to isolate a pool of nuclease-stabilized RNA aptamers enriched for TrkB agonists. One of the selected aptamers, C4-3, was characterized with recombinant protein-binding assays, cell-based signaling and functional assays, and, in vivo in a seizure model in mice. C4-3 binds the extracellular domain of TrkB with high affinity (K(D) ∼2 nM) and exhibits potent TrkB partial agonistic activity and neuroprotective effects in cultured cortical neurons. In mice, C4-3 activates TrkB upon infusion into the hippocampus; systemic administration of C4-3 potentiates kainic acid-induced seizure development. We conclude that C4-3 is a potentially useful therapeutic agent for neurodegenerative diseases in which reduced TrkB activation has been implicated. We anticipate that the cell-based aptamer selection approach used here will be broadly applicable to the identification of aptamer-based agonists for a variety of cell-surface signaling receptors.
authors: Department of Neurobiology, Duke University Medical Center, Duke University, Durham, North Carolina, USA.
authors: Yang Zhong
authors: YZ
authors: Huang
authors: Frank J
authors: FJ
authors: Hernandez
authors: Bin
authors: B
authors: Gu
authors: Katie R
authors: KR
authors: Stockdale
authors: Kishore
authors: K
authors: Nanapaneni
authors: Todd E
authors: TE
authors: Scheetz
authors: Mark A
authors: MA
authors: Behlke
authors: Andrew S
authors: AS
authors: Peek
authors: Thomas
authors: T
authors: Bair
authors: Paloma H
authors: PH
authors: Giangrande
authors: James O
authors: JO
authors: McNamara
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D059014:High-Throughput Nucleotide Sequencing; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists*; D052156:SELEX Aptamer Technique; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction; D013226:Status Epilepticus / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D052157:Aptamers, Nucleotide; D019208:Brain-Derived Neurotrophic Factor; D008024:Ligands; D018696:Neuroprotective Agents; D020813:Receptor, trkB