Aptamers that promote neuronal growth by binding to and blocking the protein Nogo
- 技术优势
- 1. Stability of DNA aptamers over protein enables better storage and long shelf-life 2. Cost-effective synthesis of DNA aptamers via efficient chemistry in large quantity, 3. Low-toxicity of DNA clearance by the body without affecting the liver 4. Higher-absorption of aptamers efficiently crossing the blood-brain barrier compared to antibody therapy
- 详细技术说明
- Damaged axons resulting from central nervous system disorders or injuries cannot regenerate because inhibitor proteins block axon regrowth. One such protein is Neuronal Growth Inhibiting Protein (Nogo), which binds to its receptor (NgR1) and induces breakdown of growth cone components thereby inhibiting axon growth. Pharmaceutical companies are developing and testing antibodies against receptor NgR1 to treat a range of disorders including spinal cord injury, stroke, ALS, and MS. These antibody proteins, however, may be unstabile, costly to synthesize and purify, and have low absorption. Alternatively, recent research describes using short RNA/DNA molecules called aptamers to block inhibition of neuron growth. The inventors discovered that single-stranded DNA aptamers effectively disrupt Nogo binding to NgR1, which increases neuron outgrowth and permits axonal repair. These aptamers were synthesized through a method of systematic evolution of ligands by exponential enrichment (SELEX) involving multiple iterations of selection, amplification, deep sequencing and synthesis of the highest occurring sequence. Some of these aptamers promote axonal growth within a period of days, and the most active aptamer developed can produce neuron growth even in nanomolar concentrations. Use of DNA aptamers may be superior to protein antibodies in terms of increased stability, cost-effective synthesis, and higher absorption in the brain to facilitate treating a range of neurodegenerative disorders.
- *Abstract
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Neuronal growth inhibiting protein (Nogo), blocks regrowth of damaged neuronal projections (axons) in neurodegenerative disorders. Currently, researchers are developing antibody proteins to inhibit Nogo and produce axon regrowth in a variety of disorders. However, such antibodies are unstable and costly to synthesize. At UCI, the synthesis of nucleic acid molecules called aptamers that selectively bind and block Nogo to promote axonal growth presents a promising alternative pharmaceutical target for treating a range of disorders including spinal cord injury, stroke, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS).
- *Principal Investigation
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Name: Melanie Cocco
Department:
Name: Andrej Luptak
Department:
- 其他
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State Of Development
In vitro studies have been performed:
§ Functional aptamers that bind Nogo have been selected for and synthesized
§ Aptamer-Nogo binding has been demonstrated to prevent inhibition of neuronal growth in a native lipid environment
§ Functional and active (nanomolar concentrations) aptamers include: Ali3, Ali4+7, Apt3-3, Apt2-2 and Apt2-1
Prospective plans involve testing additional aptamers in neuronal outgrowth and moving to in vivo mouse studies
Related Materials
Alhoshani, A; et. al. Glutamate is a Key Structural Contact Between Nogo-66 and Phosphocholine. BBA – Biomembrane. 2014, 1838, 2350. Link
Vithayathil R; et. al. The Scope of Phage Display for Membrane Proteins. J Mol Biol. 2011, 414, 499. Link
Vasudevan SV; et. al. Protein folding at the membrane interface, the structure of Nogo-66 requires interactions with a phosphocholine surface.Proc Natl Acad Sci. 2010, 107, 6847. LinkTech ID/UC Case
27175/2015-933-0
Related Cases
2015-933-0
- 国家/地区
- 美国
