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Our Science: PTEN inhibition

Traumatic Spinal Cord Injury

Spinal cord injury (SCI) is a devastating and life changing medical condition. Spinal cord injury is categorized by damage to any part of the spinal cord or nerves in the Cortical Spinal Tract (CST). When these nerves are damaged, this causes permanent changes in strength, sensation and other body functions from below the site of the injury. The reason that people remain paralyzed after spinal cord injury is that the CST cannot regenerate.

Neuroscientists agree that spinal cord injury is a problem of nerve fiber disruption. The importance of this statement cannot be overstated. For all the news stories about stem cells and other “breakthroughs,” leading researchers agree that any stem cell, factor or drug transplanted into the injured spinal cord will not cause new nerve fiber connections to grow.  Stem cell transplants will not restore the long pathway of threadlike extensions of nerve cells that conduct impulses from the brain down the central nervous system to allow for thoughtful movement. But there is hope…

Dr. He’s and Dr. Steward’s Discovery

PTEN inhibition therapy has been called the most promising spinal cord regeneration therapy so far. This scientific breakthrough discovery was initially discovered in 2008 by Dr. Zhigang He, at Harvard University. The initial discovery involved regeneration of connections from the eye to the brain (regeneration of optic nerve axons). In 2010, Dr. He in collaboration with Dr. Oswald Steward at University of California, Irvine and their research teams used the same intervention to enabled regeneration of CST axons after spinal cord injury.

Understanding PTEN Inhibition

This discovery proved regeneration of CNS (central nervous system) axons could be achieved by using a virus that contained RNA to block a molecule called phosphatase and tensin homolog (PTEN) that shuts down cell growth as an animal or human matures.

In layman’s terms, it releases “the brakes” on mTOR, and reinstates a robust regenerative capacity in the nerve cell’s axon, similar to the growth present in early development.

In layman’s terms, it releases “the brakes” on mTOR, and reinstates a robust regenerative capacity in the nerve cell’s axon, similar to the growth present in early development.

PTEN is switched off during childhood, allowing growth and development and switches on again after adolescence to prevent cellular overgrowth. Secondarily, PTEN is being studied as a potential cancer tumor suppressor gene.

Switching on PTEN after adolescence has a side effect.  It is critical in blocking nerve regeneration.  The research teams found that turning off PTEN enables unprecedented nerve regeneration, including the regeneration of the connections that control one’s ability to move voluntarily.

From Basic Science To Exciting Therapy

Dr. Steward then went on to develop a candidate therapy that effectively knocked down PTEN in rodents with acute SCI, enabling CST regeneration which was accompanied by dramatic recovery of upper extremity function in rats and mice. The Rats recovered to 95% of normal, compared with controls, which recovered to 50% of normal. The 95% recovery is by far the best result in the history of SCI research.

graph1Explanation of Recovery In “Journal Of Neuroscience” Article

This graph is from page 9 of the Journal of Neuroscience article authored by Oswald Steward and published in July 2014.  This slide depicts four different groups of rats. The numbers at the bottom depict the number of days from injury.  The animals are injured at day 1. In all groups, their gripping strength drops dramatically.  The line with the red dots is the group of animals that had PTEN inhibited and salmon fibrin inserted in the injury site.  Draw an imaginary horizontal line from the red dot at day 1 and the red dot at day 70.  After 70 days the PTEN inhibited/salmon fibrin animals recovered 95% to normal.

Explanation of Recovery In “Experimental Neurology” Article

graph2This graph is from page 11 of the Experimental Neurology article authored by Oswald Steward and published in March 2015.  In this research, the right side of the mice’s cerebral motor cortex is injured which eliminates function in the animal’s left paw.  In Graph A, follow the AAV-CRE line, which depicts the AAV which contains the shRNA to inhibit PTEN.  Draw an imaginary horizontal line from the AAV-CRE line at day 1 and the black square line at day 98.  After 98 days the PTEN inhibited left paw animals recovered better than the normal left paw animals.

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