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Breakout Session 4: Dr. Davies and Dr. Simon Archibald

Posted by katewillette on April 13, 2008

The name of the talk is Decorin and GRP-derived astrocytes.  The video Bruce made of his talk last year is on youtube, for those who want to see part A.  I’ll go find a link if I can before I post this.  This is it: http://youtube.com/watch?v=QnBsnhzy1Ug

The glial scar is a physical and molecular barrier to axon growth — a fact that’s been known for a long time.  There’s an image up from a 1999 article in the Journal of Neuroscience that shows the green lines of axons straggling toward this thing that looks like a joint in a knee, where they stop dead. It’s the injury site.

His lab has been after 2 strategies:

Overcome scar and inhibitors to promote axon regeneration/plasticity.

Replace lost glia to bridge axon growth across the injury site.

What’s the right cell type for a bridge?

Non-CNS cell types (Schwann, engineered fibroblasts, olfactory ensheathing cells, macrophages, esc’s, marrow stromal cells) plus CNS cells, and 70% of adult CNS cells are astrocytes . . . but there are different kinds. Can we make the right kind?

Embryonic Stem Cells give rise to neuron prestricted precursors and glial restricted precursors (GRPs).  GRP’s can make either GDA Bmp or GDA gp130’s

The BMP’s have low inhibitor levels, they’re high in growth factors, and highly supportive of axon growth.  The gp130’s are the exact opposite.

So, where do you get grp cells?  From esc’s, unless you can genetically engineer the adult stem cell . . .a process that is not done yet.

So when you transplant the gdabmp’s what happens?  A ton of cells migrate into the margin of the injury and they align themselves very neatly — the opposite of what happens normally, where cells are all mixed up and helter skelter. They actually measured the misalignment between axons as about 59 degrees without the astrocyte gdabmp and 11 degrees with it.

These are the same slides we saw last year, and they still knock me out. All this was published in the Journal of Biology last year, after Dr. Davies was good enough to share it with us.  So what about functional recovery? The rats that got the good astrocytes are at almost full recovery — and the ones that got the bad ones get nada.

Neuropathic Pain . . . (sometimes called allodynia) can be made WORSE by implanting “naive” neural stem cells.  They turned into grp’s, then the bad kind of astrocytes, and pain was the result.  So they tested gdabmp, gdagp130, and grp’s — the rats that got the bmp’s were like normal rats, but the others were in serious pain–so serious that they had to stop the experiment ahead of time.

This is a major reason for people to hold off on the idea of getting any kind of undifferentiated stem cell injection to get recovery.  It’s not unlikely that the result will be more neuropathic pain.

Bottom line: the bmp astrocytes are all gain and no pain. I like that combination.

Okay . . . light speed information coming our way now.  It’s the trade names of the dozen of so kinds of molecules that inhibit axon growth, some of the sugars and some of the core proteins.  The little buzzards build themselves into a kind of scaffold.  Gah, and what’s worse is that some of the molecules that had been thought important to growth carry the inhibitory molecules.

He shows an image of the cord just after injury and six months later.  The one right away shows an injury site full of molecules, and six months later the barrier is physical.

Decorin does all sorts of good things in the injury site.  It promotes the degradation of scar tissue.  It increase levels of Plasmin, which promotes axon growth, suppresses synthesis of inhibotors, promotes degradation of inhibitors, promotes increase in growth factors, desensitize neurons to inhibitors.

Here’s his new data

If you put adult sensory neurons right on the adult spinal cord myelin, they grow very slowly, but if you add some decorin, they grow 5 x faster.

AND, if you put then put them on inhibitory molecules, you get nothing (as you would expect) . . . but if you combine them with decorin and then add them to inhibitory molecules, the axons grow 14.5 times faster.  So, the magic Decorin directly boosts the ability of neurons to grow axons on both cns myelin and inhibitory molecules.  (Why does it like inhibitory molecule environment so much? Don’t know . . .)

Bottom line: gdabmp’s and decorin are new, complementary repair strategies for acute and chronic sci.

Next steps:

We need new ways to make those gdabmp’s, then test them in combination, then test them in acute and chronic, develop human gda’s at gmp level. This is looking very good — a strategy that works so well at the bench is rare.  So how long before we see this in clinical trial?  As usual, there are too many factors involved to even make an educated guess.  But if Dr. Davies’ energy for this project is related to the time frame, it will be short

Dr. Simon Archibald, chief scientific officer of Integra Life Sciences corporation.  “I used to be an academic scientist . . . my area of interest is in peripheral nerve generation and learning more about how to regenerate the cord.”  he left the academic world and went to Integra in 1997 — at the time it was a small biotech company.  They did a translation, which is the word these guys use to talk about the process of getting from a lab to a clinic.  The company grew by a factor of 20 by developing 2 main products, both of which have to do with the nervous system.

Okay, so the traditional way to do science is arcane, impractical, and slow.  (We know.)  The process of product development is not a linear list of tasks . . . it’s a mind map for those who know what those are — a jumble of blobs with looping interconnections and decision points.

Decorin was a compound that had been produced by a company that went bankrupt . . . which means that it’s been a struggle to get Decorin back on the list of “good things”.  It was famously used in 1999 by a woman in the UK who showed that it worked very well to prevent scarring in brain tissues after knife wounds.   She turned her lab over to the project of working with Decorin, but the 2nd batch she got from the supplier was bad . . .and she crashed her whole lab.

Dr. Archibald is droll, making little jokes . . . “Thank God we transcended the mice.  The little buckets and the little stools were too expensive to keep producing.”  He’s referring to the new sources of Decorin — the old one was from mice milk.  At one point their supply of mouse milk was in a refrigerator in California . . .

Integra is not a drug company, it’s a device company.  Their interest is in making the instruments that will eventually make the delivery of the treatments possible.

He’s telling us about therapies that exist to regenerate peripheral nerves, and I’m not writing down the details, altho’ it’s interesting stuff and I’m sure will one day become important to us.  My brain could totally use a bit of a transplant to juice it up at this moment.

Question: Is Dr Davies collaborating with anyone?  Other labs?  What about Keirstead’s lab?  He says he reached out but nothing has come of it as yet . . . obviously it’s a goal to speed things up by sharing information and creating joint strategies.

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One Response to “Breakout Session 4: Dr. Davies and Dr. Simon Archibald”

  1. Nice job on the blog Kate; thank you for your efforts.

    The CDRPA seems on the verge of being passed, and Obama won’t veto it, so hopefully the barriers to the science will continue to be responsibly removed and much of what is discussed above can progress to fruition. Amen!

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