Dr. Jerry Silver: Latest chronic SCI research results featured at Cleveland

[kz]

Dr. Silver , Hi, would you please check the PM I sent you and see if you can reply . Thanks

[comad]

Dr. Silver,
By my understanding, high peptide dosage safety (non-established yet)
and Viral delivery method for Ch'ase (exact procedure non exsisting - yet)
shouldn't be obstacles to design Human trial - or you have to wait for them
along with large animal trial results?
If results from UK Ch'ase dog trial shows Ch'ase effectivnes - would this be enough
so you can come closer to the human trial, or we still need to see primates trial
prior to the human trial??

Do you see any progress, any promising contacts, that might
accelerate movement toward human trial with Ch'asee + Peptide + IH or Rehab, so far?

BTW, must be hard on you when you come so close to possible cure
and would like to help so many desperate people but you need to keep
your scientific, precise calculating shield on...
You are already Hero to sharing all of this with us!!!

Please let us know how we can help?

[jsilver]

Dr. Silver,
By my understanding, high peptide dosage safety (non-established yet)
and Viral delivery method for Ch'ase (exact procedure non exsisting - yet)
shouldn't be obstacles to design Human trial - or you have to wait for them
along with large animal trial results?
If results from UK Ch'ase dog trial shows Ch'ase effectivnes - would this be enough
so you can come closer to the human trial, or we still need to see primates trial
prior to the human trial??

Do you see any progress, any promising contacts, that might
accelerate movement toward human trial with Ch'asee + Peptide + IH or Rehab, so far?

BTW, must be hard on you when you come so close to possible cure
and would like to help so many desperate people but you need to keep
your scientific, precise calculating shield on...
You are already Hero to sharing all of this with us!!!

Please let us know how we can help?

Dear Comad,

Thanks for your questions and your very kind personal comment. I am keeping my fingers crossed about the dog trial
and at the same time being cautiously optimistic. I believe the chondroitinase being used for this trial is a heat stabilized
version that allows the enzyme to remain active at body temperature for a longer time than the regular enzyme. I do not
know at what spinal level the enzyme is being delivered nor how much is being delivered. The third generation, regulated, virus delivered
enzyme will be most potent and has the ability to spread much further up and down the spinal cord. So even if the current trial
is not efficacious, I will be disappointed but far from giving up. Of course, if the dog trial shows positive effects then I would imagine
that the pace could move rather rapidly to humans without the need for primate experiments. We are doing all we can to move our peptide toward
the clinic.

[JamesMcM]

This may be a stupid question but is this "peptide" taken orally, or is it injected into the injury site on the spinal cord? Also is chase planned to be used alone or is it to be a part of the peptide?

[void]

This may be a stupid question but is this "peptide" taken orally, or is it injected into the injury site on the spinal cord? Also is chase planned to be used alone or is it to be a part of the peptide?

Watch 23:00 https://www.youtube.com/watch?v=TRlqbDNqSYc

It's injected.

A peptide is a short protein. Taking it orally would probably decompose it into aminoacids.

[jsilver]

This may be a stupid question but is this "peptide" taken orally, or is it injected into the injury site on the spinal cord? Also is chase planned to be used alone or is it to be a part of the peptide?

The peptide is delivered systemically once per day either via sub-cutaneous or intra peritoneal injection. Experiments are now underway in chronically injured animals where we are combining ch'ase and the peptide.

[GRAMMY]

The peptide is delivered systemically once per day either via sub-cutaneous or intra peritoneal injection. Experiments are now underway in chronically injured animals where we are combining ch'ase and the peptide.

Can you tell us what injury model you are using along with which kind of ch'ase is involved in these chronic experiments?

[jsilver]

Can you tell us what injury model you are using along with which kind of ch'ase is involved in these chronic experiments?

We are using a T8 severe contusive injury and then allowing the animals to age 3 months before beginning treatment. We are using regular (Sigma) ch'ase +peptide, lenti-ch'ase + peptide as well as peptide alone and lenti-ch'ase alone.

While there is some recovery with the regular ch'ase + peptide the viral ch'ase +peptide seems to be better.

[GRAMMY]

We are using a T8 severe contusive injury and then allowing the animals to age 3 months before beginning treatment. We are using regular (Sigma) ch'ase +peptide, lenti-ch'ase + peptide as well as peptide alone and lenti-ch'ase alone.

While there is some recovery with the regular ch'ase + peptide the viral ch'ase +peptide seems to be better.

Sounds great! Thanks so much.

[lynnifer]

Large animal studies already???? That is fantastic to hear for those younger than I!

[JamesMcM]

Dr. Silver I'm sure this is a very important question for most of us, but after a successful large animal study or if necessary a phase 1 safety is completed, do you think that your peptide could be given to sci patients under compassionate use? Many of us would be willing to take the risk , I mean a lot of us are praying we don't wake up... But when given a fair shot for recovery I know for a fact there's many people like myself that would go above and beyond to improve their quality of life. And as a high cervical injury every little function has dramatic implications. I understand that this is a difficult question to answer, but if you could give your best educated attempt that would be greatly appreciated.

[Nicksdad]

Their model involves the production of trails that might be used to guide axons over lengthy distances. Whether this strategy will work or not could be a topic for discussion elsewhere. Our model does not need such elaborate trail making machinery. We only need to inject via a micro needle into appropriate levels of the cord. No need for invasive procedures with our technique.

Dr. Silver, I am guessing you believe there is fault in their neuro trail theory for regeneration. I can respect that you may not want to speak negatively; but, can you elaborate a little on your concerns? It seems they too are trying to be less invasive in their application for chronics.


There is some that believe Invivo's scaffold may become the standard of care for acute injury. You have described the peptide alone as effective in the acute injury. If asked, would you consider inclusion of the peptide with the scaffold?

[jsilver]

Dr. Silver I'm sure this is a very important question for most of us, but after a successful large animal study or if necessary a phase 1 safety is completed, do you think that your peptide could be given to sci patients under compassionate use? Many of us would be willing to take the risk , I mean a lot of us are praying we don't wake up... But when given a fair shot for recovery I know for a fact there's many people like myself that would go above and beyond to improve their quality of life. And as a high cervical injury every little function has dramatic implications. I understand that this is a difficult question to answer, but if you could give your best educated attempt that would be greatly appreciated.

Dear JamesMcM,

Yes, for sure this is a difficult question that I am not able to answer. I know little about the rules that govern compassionate use. But let us first demonstrate a successful strategy that
is robust and efficacious after chronic SCI. This is the major focus of my lab.

[jsilver]

Dr. Silver, I am guessing you believe there is fault in their neuro trail theory for regeneration. I can respect that you may not want to speak negatively; but, can you elaborate a little on your concerns? It seems they too are trying to be less invasive in their application for chronics.



There is some that believe Invivo's scaffold may become the standard of care for acute injury. You have described the peptide alone as effective in the acute injury. If asked, would you consider inclusion of the peptide with the scaffold?

The sequence of our peptide is published and can be purchased by anybody. It would , indeed, be interesting to learn if it can be used in a combinatorial strategy with a bioscaffold. In regards to trail building, one of the most
perplexing phenomena that regenerating axons display is their refusal often to abandon a growth promoting surface to continue beyond the trail into the parenchyma of the gray matter in order to make functional synapses. There are techniques that have been devised to lure axons into gray matter via exogenous neurotrophins or the administration of chondroitinase at the end of the bridge to allow them to exit, but it is not clear that these additional tools are being considered. The bottom line is that trail blazing for regeneration is very complicated.

[paolocipolla]

Prof Silver,

do you think Ch'ase could work better in combination with this?

Title: Functional recovery from chronic spinal cord injury by the reactivation of endogenous microglia




During the chronic phase of spinal cord injury (SCI), fibrotic scar tissue was formed as if it was a barrier for regeneration. We hypothesized that reactivation of resting microglia, which are the resident macrophage in spinal cord, might eliminate such a structural barrier to prevent functional recovery. First, we investigated whether p38 MAP kinase (p38) could be an activator of residential microglia obtained from mice spinal cord. The addition of dominant active type of recombinant p38 protein (DA) to the culture medium promoted the activation of cultured microglia; the increased expression of growth factors including Glial cell-line derived neurotrophic factor, the phagocytotic clearance of spinal cord debris, and rapid phosphorylation of membrane protein obtained from the cultured microglia. In addition, continuous infusion of DA protein into the mice spinal cord for 7 days increased the number of Iba1-positive microglia. These results suggested that DA protein is an activator for microglia in the spinal cord. To ascertain the effect of DA protein on the chronic phase of SCI, DA injection into spinal cord was started three months after the contusion injury, and DA was injected intrathecally once a week for 2.5 months. Immunohistochemical analysis with anti-collagen antibody showed a significant reduction of scar tissue formation by long-term DA injection. Furthermore, rota rod test and BMS score revealed that DA-injected mice showed the improvement in motor function compared to the mice injected with p38 protein which lost kinase activity. These results suggest that DA protein provides a reasonable approach for functional recovery from chronic SCI by activating endogenous microglia from outside cells.
Society for Neuroscience Chicago 2015 Nanosymposium SCI: Therapeutic Strategies Trauma
Support: KAKENHI 22500340 KAKENHI 24300197 the Strategic Research Foundation Grant-aided Project for Private Schools at Heisei 23rd from the Ministry of Education, Culture, Sports, Science and Technology of Japan, 2011?2015
Authors: *M. HAMANOUE1,2, K. MORIOKA3, K. HAYAKAWA4, K. NAKAJIMA5, T. OGATA6, K. TAKAMATSU1,2; 1Dept. of Physiol., Toho University Sch. of Med., Tokyo, Japan; 2Div. of Chronic Inflammatory Diseases, Advanced Med. Res. Ctr., Toho Univ. Grad. Sch. of Med., Tokyo, Japan; 3Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), San Francisco, CA; 4Orthopaedic Surgery, The Univ. of Tokyo, Grad. Sch. of Med., Tokyo, Japan; 5Sci. and Engin. for Sustainable Innovation, Fac. of Sci. and Engin., Soka Univ., Tokyo, Japan; 6Rehabil. for the Movement Functions, Natl. Rehabil. Ctr. for Persons with Disabilities, Saitama, Japan