Regeneration 101: spinal cord axons, or nerve fibers, don’t self-repair after injury. Part of the problem is extrinsic, that is, the toxic area around the injury and the formation of an impenetrable scar. Another problem is that the axons themselves are stuck; they don’t have the juice to put forth much of an effort.
One of the major strategies in regenerative medicine for the last 25 years has centered on the notion that there are various ways to modify the inhibitory cellular environment around the injury. A good example is the molecule Nogo, aptly named by its discoverers, the Martin Schwab
lab (a member of the Reeve International Consortium on Spinal Cord Injury
). It’s easy: No Nogo, axons go. But the chemical chaos at the site of trauma is only part of the problem – just neutralizing Nogo or other molecular barriers to axon growth has only a modest effect on recovery.
Another intriguing possibility to unblock axons is to dissolve chondroitin sulfate proteoglycans (CSPGs), the main components of the glial scar that forms in the area of injury. Axons don’t get past the barrier. However, a drug called chondroitinase, or ch’ase, eats up the scar. We’ve covered this several times
: No scar, axons go. But getting ch’ase into the site of damage remains challenging
In recent a years, a new story has captured the imagination of the spinal cord cure world, and this is based on intrinsic properties of the nerve cells themselves. Novel methods based on the genetic makeup of nerve cells have been discovered to power up the ability of these cells to grow long distances and, perhaps, restore connections.
One of the cool ways nerve cells can be reenergized is by switching on their growth mode, which has not been utilized since nerves first formed when we are infants. The molecular switch is activated by deleting a gene called PTEN. We have covered PTEN research several times here, including the 2010 groundbreaking paper
from the Zhigang He lab at Harvard that showed deleting the gene promoted unprecedented growth of axons in the part of the spinal cord related to major motor function.
The He experiments have been expanded in numerous labs, including that of Os Steward at UC Irvine. The idea remains exciting but there are major technical issues. For one, in the early experiments the PTEN gene was knocked out (using a virus-delivered gene manipulation) before animals were spinal cord injured – that pretty much nullifies clinical relevance. Second, big-time growth of corticospinal axons didn’t seem to do much to improve function in paralyzed animals.
Zhigang He noted last fall
that PTEN deletion is full of promise, but alone may not be enough. It may take a combo approach: “... combining the PTEN suppression/deletion method of activating intrinsic growth with those aimed at modifying the lesion environment has great promise in improving axon regeneration,” said He.
So where are we? I recently attended the annual Meet the Scientists event at UC Irvine, home of the Reeve-Irvine Research Center. In recent years, Steward has presented information at this gathering on his PTEN work, which addresses the issues we noted: can you knock out PTEN after an injury, or even long after injury; and can you get the cortical axons to hook up and restore function?
Pending publication of research studies (soon, we were told), Steward offered little detail. He told me later that his lab is about to reveal some very encouraging results – robust upper limb recovery in an acute injury model, PTEN knocked out before injury. It’s going to be a major paper, I am sure. Too bad we can’t reveal more, but that is the nature of the scientific peer-review process.
Steward is certain PTEN can be masked out in a post-injury situation, and he’s sure the axons he’s growing are going to be able to fire up meaningful recovery. The part about being effective in chronic SCI, that's still a major puzzle.
There is something of a PTEN bandwagon in neuroscience. Poking around the literature I found this brand new paper from the Shuxin Li lab at Temple University: “The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury
I didn’t realize it until I read the credits at the end of the paper but this work was supported by a Reeve Foundation grant. The grant, from 2010, was made for studying alternatives to ch’ase for removing the scar barrier after SCI. The Li lab got funded to try out a new line of peptides that block the effect of the CSPGs.
This work with peptides apparently encouraged Li to look at the intrinsic side of the axons too: might there be ways to mask the PTEN gene and therefore boost axon growth? Well, yes, how about a PTEN peptide?
Herewith the gist of Li’s approach: he thinks the transgenic methods (e.g. the gene deletion idea) won’t translate to human patients. There are drugs that might mute PTEN, including bisperoxovanadium, but they may have nasty side effect profiles by knocking out other enzymes besides PTEN. So Li went right at PTEN, with a specific peptide.
From the abstract:
We identified PTEN antagonist peptides (PAPs) by targeting PTEN critical functional domains and evaluated their efficacy for promoting axon growth. Four PAPs bound to PTEN protein expressed in COS7 cells and blocked PTEN signaling in vivo. Subcutaneous administration of PAPs initiated two days after dorsal over-hemisection injury significantly stimulated growth of descending serotonergic fibers in the caudal spinal cord of adult mice. Systemic PAPs induce significant sprouting of corticospinal fibers in the rostral spinal cord and limited growth of corticospinal axons in the caudal spinal cord. More importantly, PAP treatment enhanced recovery of locomotor function in adult rodents with spinal cord injury. This study may facilitate development of effective therapeutic agents for CNS injuries.
Seems promising – PTEN is modified after injury, leading to recovery. Said Li, in an email:
“So far, we have tested our PTEN peptides in adult mice with dorsal over-transection SCI or with optic nerve injury. We found some axon regrowth in these mouse models following systemic treatments initiated two days after injury. If funds are available, we are planning to evaluate them in other more clinic-relevant models (such as contusion or complete SCI in rats) or in subacute/chronic SCI. Also, it is interesting to test their potential neuroprotective function or to combine them with other peptides that target scar-mediated inhibitors. Hopefully we can move some of them into clinical trials in the future.
Expect to hear much more about PTEN studies. I’ll report on the Steward lab’s experiments when the papers are out.