Jerry Silver and Other Discussion from ChinaSCINet Update

[Fly_Pelican_Fly]

PS, I appreciate you are busy. So you dont need to rush to reply to these. I too have lots to be doing

[cripwalk]

Cripwalk,

I hope that I did not offend you with my terse comment. I just wanted to remind you and others that ChinaSCINet cannot conduct first-in-human clinical trials on overseas therapies in China. We can do so in Hong Kong and Taiwan, by the way, but not in China. Please read the long missive that I wrote to Pelican. Much of that was intended for you as well.

Wise.

Wise, I am not offended in the slightest (didn't even cross my mind). I am happy to have this discussion with such a well versed individual.

I did read the reply you gave to Pelican which certainly filled in a lot of blanks.

In terms of the patents, it seems to me that there is a lot of wiggle room for licensing deals, as long as whomever is interested in the license is concerned only with research and not end game product production. Am I wrong on this?

Here's my logic:

1. Many different ch'ase patents means that there is plenty of competition between companies and the license should have a competitive price.

2. Patents expire. (14 years IIRC?)

3. There are exceptions for patents when used for a non-commercial purpose (at least in Canada anyway).

This should give researchers a little leverage on price, no? The biggest problem as I see it, is private investment firms will be unlikely to be of help because they will not own the treatment, as they would have to license it from the patent holder.

What am I missing something here?

[cripwalk]

However, in my personal opinion the market forces for drug development have changed. Money is not flowing as it once was. It's no surprise to see organisations like U2FP, ARM, PatientsLikeMe, FasterCures working at changing the status quo to liberate medical innovation from some of the daunting hurdles that exist right now. (Admittedly, you may not see them as daunting but many others do).

A question for you - with or without the $20m that CIRM are handing over to Stem Cells Inc, do you think they'll have the funding to get through a Phase III/IV if a Phase II is successful? Where will that money come from? Or do they hope that a Big Pharmaceutical will come along and give them a hand? Or maybe another handout from CIRM? And if so, what are the guarantees that the Big Pharmaceutical or other body wants to continue on the path originally set out for spinal cord injury. Money always comes with strings. Hence my pessimism.

I think this is actually a plausible outcome. Big pharma is making a lot of money from SCI, and they need them to stay sick and in chairs to continue making money. BUT, if their investment costs on a new and superior treatment is small, and efficacy is high, then I can see them buying out a smaller organization which has already done the legwork. I can at least see enough capital available to a smaller firm which is showing initial positive results.


Overall Pelican you seem very knowledgable and measured. I look forward to your future contributions.

[crabbyshark]

The herb Salidroside might be worth adding to a combination of therapies. It's protective and seems to have a beneficial effect on the nervous system.

Attached:

Protective Effects of Salidroside against Acetaminophen-Induced Toxicity in Mice

Adaptogenic and Central Nervous System Effects of Single Doses of 3% Rosavin and 1% Salidroside Rhodiola rosea L. Extract in Mice

1. Neuroreport. 2013 Jan 24. [Epub ahead of print] Salidroside promotes peripheral nerve regeneration following crush injury to the sciatic nerve in rats. Sheng QS, Wang ZJ, Zhang J, Zhang YG. aDepartment of Obstetrics and Gynecology bDepartment of Orthopaedics, Fuzhou General Hospital, Fuzhou cDepartment of Radiology, General Hospital of Ningxia Medical University, Yinchuan dDepartment of Pharmacology, Fourth Military Medical University, Xi'an, China. Salidroside (SDS), a phenylpropanoid glycoside isolated from Rhodiola rosea L., has been reported to be neuroprotective in vitro, which raises the possibility of using SDS as a neuroprotective agent after nerve injuries. In the present study, the possibly beneficial effect of SDS on promoting nerve regeneration after sciatic nerve crush injury in rats was investigated. Rats with sciatic nerve crush injury were administered intraperitoneally daily with 5 or 10 mg/kg body weight of SDS for 4 weeks. Rats that received mecobalamin or saline were considered as a positive or a negative control, respectively. Morphometric analysis of regenerated nerves and Fluoro-Gold retrograde tracing was used to evaluate axonal regeneration, whereas walking track analysis, electrophysiological assessment, and histological appearance of target muscles were carried out to evaluate the recovery of motor function. The results showed that SDS achieved functionally successful nerve regeneration in the rat sciatic nerve crush injury model, indicating that SDS holds potential as a neuroprotective agent for peripheral nerve therapies.

1. Neurochem Int. 2010 Nov;57(5):547-55. doi: 10.1016/j.neuint.2010.06.021. Epub 2010 Jul 6. Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G, Wang Z. Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi, Jiangsu, China. Beta-amyloid (Abeta) peptide, the hallmark of Alzheimer's disease (AD), invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. In this study, salidroside (Sald), an active compound isolated from a traditional Chinese medicinal plant, Rhodiola rosea L., was investigated to assess its protective effects and the underlying mechanisms against Abeta-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Abeta(25-35)-induced neuronal toxicity was characterized by the decrease of cell viability, the release of lactate dehydrogenase (LDH), morphological alterations, neuronal DNA condensation, and the cleavage of poly(ADP-ribose) polymerase (PARP) by activated caspase-3. Pretreatment with salidroside markedly attenuated Abeta(25-35)-induced loss of cell viability and apoptosis in a dose-dependent manner. The mechanisms of salidroside protected neurons from oxidative stress included the induction of antioxidant enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), and peroxiredoxin-I (PrxI); the downregulation of pro-apoptotic protein Bax and the upregulation of anti-apoptotic protein Bcl-X(L). Furthermore, salidroside dose-dependently restored Abeta(25-35)-induced loss of mitochondrial membrane potential (MMP) as well as suppressed the elevation of intracellular reactive oxygen species (ROS) level. It was also observed that Abeta(25-35) stimulated the phosphorylation of mitogen-activated protein (MAP) kinases, including c-Jun NH(2)-terminal kinase (JNK) and p38 MAP kinase, but not extracellular signal-regulated kinase1/2 (ERK1/2). Salidroside inhibited Abeta(25-35)-induced phosphorylation of JNK and p38 MAP kinase, but not ERK1/2. These results suggest that salidroside has protective effects against Abeta(25-35)-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

[NowhereMan]

The herb Salidroside might be worth adding to a combination of therapies. It's protective and seems to have a beneficial effect on the nervous system.

Attached:

Sure, sure. We can do that. Just add it to the list. UCB + lithium + methylprednisolone + ibuprofen + salidroside herbs.

[fti]

pr your opinion on the sélégiline for the stimulation of cells

http://www.ncbi.nlm.nih.gov/pubmed/22395135

http://www.ncbi.nlm.nih.gov/pubmed/22284617
more on pubmed

[Christopher Paddon]

sure, sure. We can do that. Just add it to the list. Ucb + lithium + methylprednisolone + ibuprofen + salidroside herbs.

lol..........

[crabbyshark]

Maybe Salidroside inhibits RhoA.

Effects of salidroside on expression of ROCK in rats with liver fibrosis. Xiao-Ling Wu,Wei-Zheng Zeng,Ming-De Jiang,Jian-Ping Qin,Hui Xu,Zhao Wang,Department of Gastroenterology,General Hospital of Chinese PLA,Chengdu Military Command,Chengdu 610083,Sichuan Province,China AIM:To observe the effects of salidroside on the expression of ROCK in liver tissue of CCl4-induced liver fibrosis in rats,and to explore its probable mechanism.METHODS:Ninety healthy SD rats were ran-domly divided into 3 groups:control group (n = 10),salidroside group (n = 40) and liver fi brosis group (n = 40). Experimental liver fi brosis was induced by (with the concentration of 300 mL/L soluted in liquid paraffin) subcutaneous injection of CCl4 (at the dosage of 3 mL/kg,twice per wk,8 wks). The salidroside was injected into the peritoneal cavity at the dosage of 5 mg/kg,twice per week for 8 weeks. Liver tissues from each group were stained with Masson and HEstaining to observe the collagen deposition. Expressions of ROCKⅠand ROCKⅡ in the liver tissue were detected with in situ hybridization (ISH) and immunohistochemistry (IH) respec-tively. All the figures were scanned with elec-tronic computer,and the data were analyzed with Image-Plus software.RESULTS:A signif icant collagen deposition and rearrangement of the parenchyma were noted in liver tissue of CCl4-treated rats. There were lots of pseudolobule in liver tissue. The semi-quantitative histological scores and average area of collagen were significantly increased when compared with control rats (2.1 ± 0.3 vs 3.6 ± 0.8,74.82 ± 21.51 μm2 vs 290.86 ± 89.37 μm2,both P 0.05). Compared with control group,the expressions of ROCKⅠ,ROCKⅡ and ROCKⅠmRNA,ROCKⅡmRNA were decreased significantly in salidroside group (0.203 ± 0.068 vs 0.357 ± 0.182,0.237 ± 0.056 vs 0.394 ± 0.238; 0.197 ± 0.019 vs 0.394 ± 0.238,0.185 ± 0.031 vs 0.279 ± 0.112,P 0.05 or 0.01).CONCLUSION:The expressions of ROCK Ⅰ and ROCK Ⅱ in liver tissues are inhibited significantly with salidroside treatment. Salidroside could interfere with the signal transduction of Rho-ROCK pathway and then inhibit liver fibrosis in rats.

Attached:

1. Science. 2003 Nov 14;302(5648):1215-7. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B. Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. zhou_yan_yz@lilly.com A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity.

1. Behav Brain Res. 2013 Feb 5. pii: S0166-4328(13)00064-8. doi: 10.1016/j.bbr.2013.01.037. [Epub ahead of print] Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Zhang J, Zhena YF, Pu-Bu-Ci-Ren, Song LG, Kong WN, Shao TM, Li X, Chai XQ. Department of Neurology, The First Affiliated Hospital of Hebei Medical University, Shijiazhuang 050017, China. Beta amyloid (Aβ)-induced oxidative stress and chronic inflammation in the brain are considered to be responsible for the pathogenesis of Alzheimer's disease (AD). Salidroside, the major active ingredient of Rhodiola crenulata, has been previously shown to have antioxidant and neuroprotective properties in vitro. The present study aimed to investigate the protective effects of salidroside on Aβ-induced cognitive impairment in vivo. Rats received intrahippocampal Aβ(1-40) injection were treated with salidroside (25, 50 and 75mg/kg p.o.) once daily for 21 days. Learning and memory performance were assessed in the Morris water maze (days 17-21). After behavioural testing, the rats were sacrificed and hippocampi were removed for biochemical assays (reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), acetylcholinesterase (AChE), acetylcholine (ACh)) and molecular biological analysis (Cu/Zn-SOD, Mn-SOD, GPx, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear factor κB (NF-κB), inhibitor of κB-alpha (IκBα), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), receptor for advanced glycation end products (RAGE)). Our results confirmed that Aβ(1-40) peptide caused learning and memory deficits in rats. Further analysis demonstrated that the NADPH oxidase-mediated oxidative stress was increased in Aβ(1-40)-injected rats. Furthermore, NF-κB was demonstrated to be activated in Aβ(1-40)-injected rats, and the COX-2, iNOS and RAGE expression were also induced by Aβ(1-40). However, salidroside (50 and 75mg/kg p.o.) reversed all the former alterations. Thus, the study indicates that salidroside may have a protective effect against AD via modulating oxidative stress and inflammatory mediators.

[nrf]

Sure, sure. We can do that. Just add it to the list. UCB + lithium + methylprednisolone + ibuprofen + salidroside herbs.

Don't forget Aspirin, blue M&M's, lowering the core temperature, Enbrel and rubbing of feet!

[Wise Young]

I hope so. Speaking from experience, most participants in the West that take part in a clinical trial as intrusive as an intra-spinal cell transplant are motivated by the probability of functional or sensory return rather than their noble contribution to the scientific field. Maybe I'm meeting and talking to the wrong people.

• Of course most people hope, as I do, that the therapy will restore function. But, there is also a sense of altruism in volunteering for clinical trials amongst many of the people who have participated in our clinical trials.

You have a lot more faith in the commercial model than I do. Probably because you have seen a number of therapies make it through the pipeline successfully (MP, 4-AP). So from your perspective, it's not impossible. Fair enough.

However, in my personal opinion the market forces for drug development have changed. Money is not flowing as it once was. It's no surprise to see organisations like U2FP, ARM, PatientsLikeMe, FasterCures working at changing the status quo to liberate medical innovation from some of the daunting hurdles that exist right now. (Admittedly, you may not see them as daunting but many others do).

• I am glad that some organizations are working to find alternative routes towards restorative therapies for spinal cord injury. I do wish them the greatest success but point out that none have yet to yield a meaningful therapy for spinal cord injury. The spinal cord injury community must not abandon or be ignorant of how the trillion dollar therapeutics industry is organized and motivated. Many disease communities, such as those with multiple sclerosis and AIDS, have successfully convince the therapeutics industry to invest billions into the development of therapies for them. The spinal cord injury community should do so as well.

A question for you - with or without the $20m that CIRM are handing over to Stem Cells Inc, do you think they'll have the funding to get through a Phase III/IV if a Phase II is successful? Where will that money come from? Or do they hope that a Big Pharmaceutical will come along and give them a hand? Or maybe another handout from CIRM? And if so, what are the guarantees that the Big Pharmaceutical or other body wants to continue on the path originally set out for spinal cord injury. Money always comes with strings. Hence my pessimism.

• I am sure that your question is rhetorical, so let me answer it with a another rhetorical question. How do you think that all clinical trials are done? You do it one step at a time, convince one donor at a time, deal with one naysayer at a time, obtain the commitment of one company at a time, recruit one doctor at a time, and complete one trial at a time against all odds. I have been working on ChinaSCINet for nearly 10 years (I started in 2003). We will complete the first phase III trial of the first combination cell transplant and drug therapy for chronic spinal cord injury. We will find therapies that work and then keep on finding better ones. That is the way it is. We have no sugar daddies and no guarantees. I think that it is great that CIRM handed $20 million to Stem Cell Inc. Nobody handed $20 million to ChinaSCINet. I hope that Stem Cell Inc. makes the most of it and doesn't give up after the phase II. I know that ChinaSCINet will succeed because our goal is not to make money but to find therapies that work.

Incidentally, it is much harder to initiate and do clinical trials within companies. Within companies, the competition and fighting for internal resources is fierce, probably fiercer and harder than outside of companies because champions of therapies within companies are limited to therapies made by the company, have no other source of funding, and must convince the leadership of the company that the therapy is not only safe and effective but will make a lot of money. Few companies have the patience to wait even 6 years for a return on their investment.

This is always going to be a two-way relationship. These days large philanthropic investors want to see business plans, milestones and returns on investment (not financial) - just like any VC. These people do exist. However, it's up to researchers and the Community to pitch these projects to them in a compelling manner. Otherwise, we sit and wait for small and medium-sized biotechs struggle along looking to work the markets to raise funds to translate therapies to the bedside. Putting my faith in these small entities to facilitate a Cure for chronic spinal cord injury makes me very very nervous.

• The venture capital industry died in 2008 and has not yet arisen from the flames. I recently shared a podium with my friend Jonas Wang, who is the CEO of Stemcyte and managing partner for Sycamore Ventures, the largest venture capital firm in New Jersey. He said something that shocked me. Since 2008, no venture-backed biotechnology company has had a successful initial public offering (IPO). Venture companies have closed most of their biotech venture funds and are simply waiting for the economy to turn up so that they can sell their stakes in the few companies that have survived.

For the better part of two decades, big pharma has used biotech companies to de-risk therapies before they acquire them. This model turned out to be inefficient and expensive, contributing significantly to the >$2 billion price to move a therapy from discovery to market. The industry is now looking for better models. I believe that the best model is non-profit clinical trial networks that are supported by a diversity of sources to test the most promising therapies efficiently and rigorously.

If the murky patent/license issues could be solved, I think a consortium to fund Ch'ase would be very do-able. As you say, the situation is a lesson that we should all learn from. If you're breaking things down to basics, intellectual property always comes second to humanity. I'd hope you would agree with that.

I am glad that SCINetChina is ready to take Ch'ase to trial. Let's see where ISRT take us next for this particular line.

• Agree.

I suppose some researchers will say, why not try in a larger animal model whereby umbilical cord blood can be sourced? Therefore conflict will no doubt come with the territory.

We've seen similar conflict between researchers on the need to perform non-human primate studies before human trials.

• Why delay the trials for another several years when it will not change the design of the trials and the safety of the treatment has been shown? Umbilical cord blood from dogs have been injected into spinal cords of experimentally injured dogs at a week after injury in Taiwan and in Korea. The results indicate that umbilical cord blood cell transplants are be safe and improve recovery in dogs. However, the transplanted cord blood cells were not HLA-matched and they did not transplant the cells into chronically injured dogs. There is no dog cord blood bank and dog studies are difficult and expensive. The only spinal cord injury treatment efficacy dog studies that I know in the United States are actual clinical trials on naturally spinal-injured dogs at Purdue and in Austin, TX.

Does the Chinese FDA stipulate a minimum duration between completion of Phase II and start of a Phase III?

• No. I don't think the U.S. FDA or EMA requires any delay either? Why do you ask?

I find it hard to get my head around moving to a Phase III without any evidence of motor or sensory recovery in Phase II. (Although I agree, we have to wait until we see the 12 month data before making the assumption that there will be no motor or sensory).

FYI If you decide to move forward to a Phase III solely based on increased CPG-activated walking - then I personally wouldn't agree with that as I do not consider this as an appropriate outcome. I regard stepping and functional walking as two very different things. I dont say this flippantly but rather from my first hand experience. It's not an outcome I feel is synergistic with CST regeneration. But that's just my opinion and I have the same opinion of epidural stim btw. I dont like the term "locomotor recovery" as it has elements of grey.

Hopefully we will see motor and sensory scores change in the Phase II data and this point will be moot

• Please withhold judgment until the data is available. Thank you.

These are excellent questions Wise. Is Acorda actually considering these things or are we expecting someone else to do it? If Ch'ase or any other line of science is indeed stuck in "purgatory" it's logical to look for alternatives. Now, the question from us is who all is discussing these alternatives in terms of translation and pre-clinical strategies? Or are we just shooting the breeze and waiting for some commercial entity to come along and lead this?

• I have given you evidence that Acorda is seriously investing in development of better chondroitinase. When they are ready, they will announce their trials.

Thanks for the explanation. Very interesting. I assume that the mechanism of action is always a moving target as the basic science surges forward.

Wise, do you know for a fact that the Seigakaku enzyme will not meet FDA purity criteria for the cord?

Thanks for explaining Ch'ase patent situation. I agree there are lessons to be learned for commercial entities, community members and researchers in this case. I hope we do not see more cases like this in the future.

• You are welcome. Regarding Seikagaku, I don't think that they have applied to the FDA to use their formulation to inject into the spinal cord. Also, there is no reason why Seikagaku would be willing to provide its formulation or even its safety data to Acorda or any other company. This is not an unusual situation and there will be many cases like this in the future.