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Publications on KCC2, Activating Spared Tissue, PTEN Inhibition and Nerve Regeneration

Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations

Bo Chen, Yi Li, Bin Yu, et. al. Cell 174, 521–535
July 26, 2018 Spared tissue can be reactivated with the drug KCC2. This research identified inhibitory interneurons as a roadblock to signals from the brain to descending circuits.

Neuronal PTEN deletion in adult cortical neurons triggers progressive growth of cell bodies, dendrites, and axons

Gallent, E. and Steward, O. (2018).   Exp. Neurol., 303, 12-28.
Robust neuronal growth can be induced in fully mature cortical neurons long after the developmental period has ended and this continuous growth occurs without obvious functional impairments.

Modest enhancement of sensory axon regeneration in the sciatic nerve with conditional co-deletion of PTEN and SOCS3 in the dorsal root ganglia of adult mice

Gallaher, Z.R., and Steward, O.  (2018) Exp. Neurol., 303, 120-133
This paper demonstrates that deletion of PTEN and SOCS3 in dorsal root ganglion neurons modestly boosts naturally-occurring regeneration of peripheral nerve axons following crush injury.  Importantly, and in contrast to the situation in the optic nerve crush model (Sun et al., 2011), deletion of PTEN alone was nearly as effective as co-deletion of PTEN and SOCS3.  This is important in terms of developing a candidate therapy because targeting only one gene is likely to have a better safety profile than targeting two genes.

Selective neuronal PTEN deletion: Can we take the brakes off of growth without losing control?

Gutilla, E. A., and Steward, O. (2016)  Neural Regeneration Research. 11(8): 1201–1203.
This paper reviews the evidence that PTEN inhibition can enable functional regeneration without adverse consequences.

Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice

article-thumb-experimental-neurology-2016Gutilla, E.A., and Steward, O. Experimental Neurology (2016).
This was an initial safety study testing whether there were adverse consequences of permanent genetic deletion of PTEN in the way that enabled axon regeneration.  There was no evidence of tumors or any other neuropathology in rats that survived 18 months after PTEN deletion in the cortex, which is over half of a rat’s normal lifespan. Cortical neurons in which PTEN had been deleted for over 1.5 years appear robust and healthy.

PTEN Deletion Promotes Regrowth of Corticospinal Tract Axons 1 Year after Spinal Cord Injury

article-journal-neuroscience-2015Kaimeng Du, et al, Journal of Neuroscience (July 2015).
Dr. Liu is the first author on the 2010 Nature Neuroscience article which described regeneration in the corrticospinal tract. At the time Dr. Liu was a post doctoral reseacher in Zhigang He’s lab at Harvard University. Dr. Liu set up his own lab at Hong Kong University. He has been studying PTEN inhibition in chronic spinal cord injury. In this current article from Journal of Neuroscience, Dr. Liu shows robust regeneration at seven months after PTEN inhibition in chronic spinal cord injured mice.

Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice

article-experimental-neuology-2015Danilov, C.A., Steward, O. Experimental Neurology (2015).
This paper demonstrates that regeneration and recovery of upper extremity function are enabled by interventions targeting PTEN in a therapeutically relevant time frame just after a spinal cord injury.  This paper is also important because it confirms the key findings of Lewandowski regarding effectiveness of PTEN inhibition in enabling regeneration and functional recovery.

AAVshRNA-Mediated Suppression of PTEN in Adult Rats in Combination with Salmon Fibrin Administration Enables Regenerative Growth of Corticospinal Axons and Enhances Recovery of Voluntary Motor Function after Cervical Spinal Cord Injury

article-journal-neuroscience-2014Lewandowski, G. and Steward, O. Journal of Neuroscience (July 2014)
This paper demonstrates that CST regeneration and recovery of skilled motor function can be achieved by knocking down PTEN with an AAVshRNA vector which in theory can be used in any species.   This is an important milestone on the road to a candidate therapy.  This paper is also important because it establishes the key animal model involving spinal cord injuries at the cervical level and recovery of upper extremity function (reaching and grasping), which would be life-changing for people whose arms and hands were paralyzed due to cervical SCI.

PTEN deletion enhances the regenerative ability of adult corticospinal neurons

Liu et al., Nature Neuroscience (September 2010)
This is the paper that was published in the September 2010 Nature Neuroscience. Papers published in Nature undergo the highest level of scrutiny and peer review. A photo of the nerve regeneration achieved by Drs. He and Steward made the cover of the September 2010 issue.

Other articles about PTEN Inhibiton

Sustained axon regeneration induced by co-deletion of PTEN and SOCS3

Sun, et al., Nature (2011).
In a follow-up to the original study by Park et al., 2008, in this paper, Dr. He and colleagues show that deleting another gene called SOCS3 also enables regeneration of optic nerve axons following crush injury..

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie et al., The Journal of Neuroscience (July 7, 2010).
This paper reports injection of a drug that blocks PTEN activity into an injured peripheral nerve in rodents enhances the limited regeneration that occurs without treatment.

SOCS3 Deletion Promotes Optic Nerve Regeneration In Vivo

Smith et al., Neuron (2009).
In a follow-up to the original study by Park et al., 2008, this paper by Dr. He and colleagues shows that deleting another gene called SOCS3 also enables regeneration of optic nerve axons following crush injury.

Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway

Park et al., Science (November 2008)
This paper reports the breakthrough discovery by Dr. He’s research team showing that PTEN inhibition enables unprecedented regeneration of optic nerve axons.  The optic nerve crush model is extensively used to test interventions to enable regeneration of adult CNS axons.

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