Peptides that Enhance Acetylcholinesterase Expression
Richard L. Rotundo and Carlos A. Ruiz
Problem
Acetylcholinesterase (AChe) inhibitors such as the nerve agents sarin, soman, tabun and VX are easily synthesized compounds that can be used by anarchists and terrorist groups to inflict widespread injury on civilian and military populations. In addition, several tens of thousands of fatalities occur each year through the improper use of related pesticides such as malathion and parathion. Treatments for such injuries, as well as protection of first responder emergency personnel, are of urgent need.
Solution
The fact that AChe expression is enhanced by the peptides described in this invention makes them the only natural protection against toxic effects due to AChe inhibitors.
Competitive Advantage
This is the only method that neutralizes toxic effects of nerve gas and pesticides by increasing levels of a naturally occurring enzyme. Furthermore, this is the only approach that can be used preventively, thus increasing the chance of survival of first responders.
Applications
This invention uses peptides based on the amino terminal domain of the acetylcholinesterase subunits ColQ and PRiMA together with an endoplasmic reticulum localization signal. When these peptides are administered to tissue cultured cells, the expression of AChe is enhanced several fold. These peptides can be used to increase AChe expression to enhance: 1. Recovery of acetylcholinesterase following pesticide poisoning and nerve agent exposure. 2. Circulating acetylcholinesterase levels in emergency medical first responders and pesticide workers. 3. Tolerance to nerve agents or pesticides. 4. Treatment of patients with Congenital Myasthenia with AChe Deficiency.
Patent Status
International Patent Application No.
WO2008088385
entitled "PEPTIDES THAT ENHANCE ACETYLCHOLINESTERASE EXPRESSION" was published on July 24, 2008.
Licensing Opportunity
We are seeking collaborative research and commercial options to further develop this technology.
About the Inventors
Richard L. Rotundo, Ph.D., received his Ph.D. from the University of Connecticut in 1976. He then worked at the Carnegie Institution of Washington before joining the University of Miami as an Assistant Professor in 1984. Since 1993, he has been a Professor of Cell Biology and Anatomy, Physiology and Biophysics, and a member of the Neurosciences Program at the University of Miami Miller School of Medicine. His major areas of research concern the biogenesis, assembly, localization and regulation of acetylcholinesterase in nerves and muscle, and the development of nerve-muscle synapses including assembly of the specialized extracellular matrix to which the acetylcholinesterase molecules attach. He is a leader in the field of acetylcholinesterase molecular and cellular biology and is a frequent lecturer and consultant in this area. In addition, he has been a member of NIH scientific review panels as well as a member and chair on panels reviewing the United States Army Medical Research Institute of Chemical Defense's research program that is responsible for developing protection against nerve agents. His insights into this area have lead to novel strategies for protection and treatment of organophosphate poisoning.
Carlos A. Ruiz is a graduate student who works on the post-translation regulation of acetylcholinesterase synthesis and assembly and is the recipient of an NIH Kirschstein National Research Service Award.
Selected References
Kimbell KM, Ohno K, Engel AG, and Rotundo RL. C-terminal and heparin-binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse. J. Biol. Chem. 2004; 279: 10977-11005.
Rotundo RL. Expression and localization of acetylcholinesterase at the neuromuscular junction. J. Neurocytology. 2003; 32: 743-766.
Arikawa-Hirasawa E, Rossi SG, Rotundo RL, and Yamada Y. Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice. Nature Neuroscience. 2002; 5: 119-123.
Jacobson C, C?t￩ P, Rossi SG, Rotundo RL, and Carbonetto S. The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basal lamina. J. Cell Biol. 2001; 152: 435-450.
