Amarantus Bioscience Holdings Inc (AMBS)

[joboggi]

MJFF is firm with their notion that NFs probably have to go through an alpha syn model. ( Email correspondence ) Now, they are currently testing NFs. And if you look down they are testing a HUGE range of compounds, and so, eventually, I expect that no stone will remain unturned, including MANF for PD despite the total failure of other NFs in their treatment of PD to date.

(First since this is getting long. I am going through and copy pasting different topics I have touched upon regarding AMBS for use as a sticky. This will continue to be updated and is updated because of the recent Ad conference on Lympro. Overall this is a positive post. It is also complicated.However it is decidedly LESS positve now. Before I thought they would get a couple of million a year from Lympro, now there is next to no hope of revenue ever, from Lympro. In the next iteration, I am going to make individual posts for each topic, and link them together, so you can more easily pick the topic you want to cover. So back to the action.)

This is my email to MJFF. It was answered by an associate director in charge of research partnerships at MJFF. May 2013

"It continues to befuddle me. Why on earth does the human treatment with various compounds follow testing in rats who have a chemical ablation of their SN and the like. PD is an alphasynucleopathy. Until a rat model of this is made, you are not going to get good results with disease modifiers.

n'est pas?"
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"Thank you for your interest in PPMI![color=red] We agree [with sic] you completely,[/color] and are currently working on efforts to develop models of synucleinopathy. Please feel free to sign up for our PPMI newsletter for up to date information about the study (http://www.ppmi-info.org/get-email-updates/)

Please feel free to contact us if you have any other questions.
Best,
Vanessa
Vanessa Arnedo
Associate Director, Research Partnerships
THE MICHAEL J. FOX FOUNDATION FOR PARKINSON’S RESEARCH

Except for the part that includes my actual email address, that is the entire email that I received from the associate director of research partnerships at the MJFF. Note she is into research partnerships.
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regarding the issue of MANF and PD

There is one other MJFF reference that is important to this topic.

MJFF does not think that the most recent conclusion regarding Improvement in pathology in their study reported in Nov 2012 is supported by the data. MJFF did reserve the right to change their mind, based on future data. So we will see. However, the Exhibit 99.1 of the Dec 27 SEC 8k filing stands.

That statement refers to the MJFF interpretation of the study they helped support of MANF in PD. See the entire Exhibit for more details. Again, while they reserved the right to change their mind, in 18 months, they have chosen not to do so.
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These two issues have not been considered in the many writings of JN from Seeking alpha. This impacts the market value of MANF as it pertains to PD. MANF in PD has been tested on the chemical model of PD, not the alphasynuclein model of PD. This is becoming the accepted model of PD.

For some time now, medicine created a category called Alphasynucleopathies.

PD is an alphasynucleopathy. Now, it is not known, in all cases, what causes this pathology, but there are a number of similar diseases that share a similar pathology.

https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?alpha-synuclein

Note that MJFF itself spent $47 million on Alpha syn research so far.

www.fasebj.org/content/18/6/617.full
http://www.jbc.org/content/283/14/9089.full.pdf+html
http://www.jneurosci.org/content/27/47/12808.full.pdf+html
http://www.jneurosci.org/content/26/36/9227.full.pdf+html
http://www.jbc.org/content/281/7/4117.full.pdf+html
http://hmg.oxfordjournals.org/content/14/7/967.full.pdf+html
http://www.pnas.org/content/105/25/8637.full.pdf+html
http://hmg.oxfordjournals.org/content/17/23/3784.full.pdf+html
http://www.jbc.org/content/285/20/14941.full.pdf+html


http://www.ncbi.nlm.nih.gov/pubmed/14502652

"
The term synucleinopathies is used to name a group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). Clinically, they are characterized by a chronic and progressive decline in motor, cognitive, behavioural, and autonomic functions, depending on the distribution of the lesions. Because of clinical overlap, differential diagnosis is sometimes very difficult. Parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of DLB and MSA. Autonomic dysfunction, which is an isolated finding in PAF, may be present in PD and DLB, but is usually more prominent and appears earlier in MSA. DLB could be the same disease as PD but with widespread cortical pathological states, leading to dementia, fluctuating cognition, and the characteristic visual hallucinations. The deposition of aggregates of synuclein in neurons and glia suggests that a common pathogenic mechanism may exist for these disorders. Even though synuclein may play an important role in disease development in these disorders, in light of the different symptom complex and prognosis and management issues that characterize each disorder, we think that the term synucleinopathy has little practical value as a diagnostic term for the clinician. Clinicians should attempt to reach standard clinical diagnosis on patients, such as PD, PAF, or MSA"



"
Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the alpha-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson's disease (PD). Subsequently, other mutations in the alpha-synuclein gene have been identified in familial PD. The aggregated proteinaceous inclusions called Lewy bodies found in PD and cortical Lewy body dementia (LBD) were discovered to be predominantly alpha-synuclein. Aberrant aggregation of alpha-synuclein has been detected in an increasing number of neurodegenerative diseases, collectively known as synucleopathies. Alpha-synuclein exists physiologically in both soluble and membrane-bound states, in unstructured and alpha-helical conformations, respectively. The physiological function of alpha-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. Abnormal processing of alpha-synuclein is predicted to lead to pathological changes in its binding properties and function. In this review, genetic and environmental risk factors for alpha-synuclein pathology are described. Various mechanisms for in vitro and in vivo alpha-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored."

http://www.ncbi.nlm.nih.gov/pubmed/15737408
http://www.ncbi.nlm.nih.gov/pubmed/11193145
http://www.ncbi.nlm.nih.gov/pubmed/14502650
http://www.ncbi.nlm.nih.gov/pubmed/15094295
http://www.ncbi.nlm.nih.gov/pubmed/12794302


So while we do not know what causes the alpha syn difficulty in all cases, this is associated with PD. The FASBEJ article is particularly good at going over the next level of detail in this regard and there are literally hundreds if not thousands of articles on this topic.

Now, since they do not know what causes the alpha syn in all cases, there may be another agent or process that causes that pathology to ensue.

So, in that sense, they do not know what causes PD, but in a more general sense, they have known for some time a lot of what causes PD in the human body, and it has nothing at all to do with the chemical model induces in rats.

I would submit that is why ALL of the NFs have failed in Humans. ( Some trials are ongoing as noted )

As best as I can evalutate, after reading enough of the literature to make a reasonable assessment, MANF is a reactant to the inflammation and death caused by the mutant alpha syn. As it helps with cell death in the ER in other processes, it does so in PD, but it ultimately fails.

That means it helps a little in delaying the onset of PD, but ultimately fails because it does not attack the root cause. Difficulties with delivering MANF will more than likely keep it from being a disease modifier for PD.

However, it is reasonable to test MANF in primates to see what will happen. It is also reasonable to test it against Alpha syn. To that end, it will get research dollars.

We've known about alpha syn for more than 10 years but for some reason the main focus of research has NOT gone through alpha syn. That has wasted a lot of money on GDNF and Neurturin. That is changing however.
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Here is a list of compounds currently on trial at MJFF. You will note that they are trying everything really, even bee venom and things that could possibly work, but may not.

They are addressing Alpha Syn, along with other avenues. Note the NF studies that are still running. This particular graphic does note they are in phase I for an Alpha syn vaccine ( second link )

https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?therapies-in-development

https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=896

https://www.michaeljfox.org/research/research-tools-catalogue.html?viralvector=true
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An understanding of the current range of causes of PD is needed to understand why MANF may or may not work in PD. This is from an electronic medical text book, so it is a little bit more technical than the MJFF page on causes of PD. There is an entire section in this electronic medical text book on alpha syn as a probably cause of PD.

http://emedicine.medscape.com/article/1831191-overview#aw2aab6b2b5
Etiology


Although the etiology of Parkinson disease is still unclear, most cases are hypothesized to be due to a combination of genetic and environmental factors. Currently known genetic causes of Parkinson disease account for approximately 10% of cases.

Environmental causes

Environmental risk factors commonly associated with the development of Parkinson disease include use of pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and proximity to industrial plants or quarries.[4]

A meta-analysis of 89 studies, including 6 prospective and 83 case-control studies, found that exposure to pesticides may increase the risk for PD by as much as 80%.[5, 6] Exposure to the weed killer paraquat or to the fungicides maneb or mancozeb is particularly toxic, increasing the risk for PD about 2-fold. Many of the agents studied are no longer used in the United States and Europe; however, some are still found in developing parts of the world.[5, 6]

In case-control studies, PD was associated with exposure to any type of pesticide, herbicide, insecticide, and solvent, with risks ranging from 33% to 80%.[5, 6] Increased PD risk was also associated with proxy conditions of exposure to organic pollutants, such as farming, well-water drinking, and rural living. In addition, risk seemed to increase with length of exposure.[5, 6]

The National Institutes of Health-AARP Diet and Health Study, as well as a meta-analysis of prospective studies, found that higher caffeine intake was associated with lower risk of Parkinson disease in both men and women. A similar association was found for smoking and Parkinson disease risk.[7] The biological mechanisms underlying the inverse relationship between caffeine or smoking and Parkinson disease risk are not well elucidated.

MPTP interference with mitochondrial function

Several individuals were identified who developed parkinsonism after self-injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks and improved with dopamine replacement therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B.[8]

MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a cause of Parkinson disease, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism.

Oxidation hypothesis

The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the development or progression of Parkinson disease. The oxidative metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Normally, hydrogen peroxide is cleared rapidly by glutathione, but if hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In Parkinson disease, levels of reduced glutathione are decreased, suggesting a loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals.

Parkinson disease is associated with increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. This hypothesis has raised concern that increased dopamine turnover due to levodopa administration could increase oxidative damage and accelerate loss of dopamine neurons. However, there is no clear evidence that levodopa accelerates disease progression.

Genetic factors

If genetic factors are important in a particular disease, concordance in genetically identical monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early Parkinson disease twin studies generally found low and similar concordance rates for MZ and DZ pairs.

However, genetic factors in Parkinson disease appear to be very important when the disease begins at or before age 50 years. In a study of 193 twins, overall concordance for MZ and DZ pairs was similar, but in 16 pairs of twins in whom Parkinson disease was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant.[9]

The identification of a few families with familial Parkinson disease sparked further interest in the genetics of the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene.[10] Termed PD-1, this mutation codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of tremor, and good response to levodopa therapy.[10] Five small Greek kindreds were also found to have the PD-1 mutation.

In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein gene can cause Parkinson disease.[11] A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively called PARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease.

A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are well-validated causes of familial parkinsonism.[12] Inheritance is autosomal dominant for SNCA and LRRK2 (although LRRK2 mutations exhibit variable penetrance). Inheritance is autosomal recessive for PRKN, DJ1, PINK1, and ATP13A2. In addition, polymorphisms within SNCA and LRRK2, as well as variations in MAPT and GBA, are risk factors for Parkinson disease.[12]

(For more information on genes/loci underlying monogenic parkinsonism and susceptibility genes/loci for Parkinson disease, see Tables 1 and 2, respectively, in The Genetics of Parkinson Disease.[12] )

In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64 patients (6.7%) had a PRKN mutation, 1 patient (0.2%) had a DJ1 mutation, 35 patients (3.6%) had an LRRK2 mutation, and 64 patients (6.7%) had a GBA mutation.[13] . Mutations were more common in patients with age at onset of 30 years or younger (40.6%) than in those with age at onset between 31 and 50 years (14.6%); more common in patients of Jewish ancestry (32.4%) than in non-Jewish patients (13.7%); and more common in patients reporting a first-degree family history of Parkinson disease (23.9%) than in those without such a family history (15.1%).[13]

Although the mechanisms by which genetic mutations cause Parkinson disease is not known, evidence to date converges on mechanisms related to abnormal protein aggregation, defective ubiquitin-mediated protein degradation, mitochondrial dysfunction, and oxidative damage.

Alpha-synuclein conformational changes and aggregation

Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are characteristic pathologic findings in Parkinson disease. Missense mutations and multiplications in the SNCA gene that encodes alpha-synuclein, although rare, cause autosomal dominant Parkinson disease. However, genome-wide association studies have also demonstrated a link between SNCA and sporadic Parkinson disease.

Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and understanding its relationship to the disease process holds major promise for the development of a cure.

Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when bound to membranes or vesicles containing acidic phospholipids, it takes on an alpha-helical structure. Normally, alpha-synuclein is found mainly in neuronal presynaptic terminals and may play a role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) proteins that are involved in neurotransmitter release.

Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted to the beta–sheet-rich fibrillary structures that form Lewy bodies and neurites in Parkinson disease. Most evidence currently suggests that it is the intermediate soluble oligomers that are toxic to neurons.

Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein could exert neurotoxicity.[14] One hypothesis suggests that oligomeric alpha-synuclein can promote formation of ion-permeable pores on neuronal membranes, leading to increased calcium influx. Aberrant pore formation could also lead to neurotransmitter leaks from synaptic vesicles into the cytosol. In addition, overexpression of alpha-synuclein has been demonstrated to impair mitochondrial complex I activity, and oligomeric alpha-synuclein may have a direct effect on mitochondrial membranes. Other lines of evidence suggest that oligomerization of alpha-synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing protein, tau.[15]

Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated by a balance between synthesis and degradation. SNCA multiplications lead to increased synthesis of alpha-synuclein and can cause Parkinson disease. Alpha-synuclein appears to be degraded by the ubiquitin proteasome system and the autophagy-lysosome pathway. Several genetic mutations associated with Parkinson disease may lead to decreased alpha-synuclein degradation. For example, increased risk of Parkinson disease in carriers of GBA (beta-glucocerebrosidase gene) mutations, which encode for the lysosomal enzyme glucocerebrosidase, may be due to lysosomal dysfunction and consequent alpha-synuclein accumulation and oligomerization.
[color=blue]
How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a prionlike process in which misconformed proteins induce the templated misfolding of other protein molecules. In Parkinson disease, synuclein pathology begins in the lower brainstem and olfactory bulb, ascends up the midbrain, and eventually affects the neocortex. One set of observations in support of a prionlike process comes from experience with fetal dopaminergic grafts transplanted into the striata of patients with Parkinson disease, because these grafts develop Lewy bodies, suggesting host-graft transmission of disease.[16]

Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping Parkinson disease progression." [/color]
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Next RP
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RP - is terribly indolent. Given that MANF shows improvement in the pathology in RP I suspect that it will work in humans here, because the damage is not yet done in RP. In Parkinson's and in Wolframs, the damage is already done by the time you find the patient. In RP, while the conclusion is inevitable, blindness takes decades to develop.

Now MANF if competing with Rx that are already in humans that are showing positive results. HOWEVER, for a number of reasons, there is reason to believe that MANF will work for RP. Where it fits in the scheme is yet to be determined.

RP is about 1 in 3000. That means there are about 115000 in the US and a million and a half in the world. At $100000 a treatment per year you have a blockbuster drug. Given the indolence of RP, it is likely that MANF will work here if it works anywhere. The economics also makes sense for Rx of RP so this is the number one indication on the list in my opinion.
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Wolfram's

This is a genetic disease. While MANF does show improvement in the ER in the pancreas that may delay the DM, there are standard treatments, that are not expensive for DM. A biologic like MANF would be very expensive treatment. It would have to cure the DM in Wolfram's which is caused by the genetic disorder that causes Wolframs in the first place, and so I doubt that a cure would ensue.

For DM, MANF is a treatment, and not a cure for Type I DM it is in competition with the bionic Pancreas. This is a link to just one of the many groups working on this issue. This group predicts a product in 2017. Bionic pancreas is a combination of a continuous glucose monitor, an insulin pump and a glucagon pump run by a smartphone or tablet. They are fine tuning their product, along with many others who are doing the same thing.

http://www.artificialpancreas.org/Home_Page.html

Continuous Glucose monitoring measures your blood glucose every five minutes. An algorithm is in place that specifies how much Insulin is needed. Given that they have a lot of experience now in programming, the computer that runs this, they are able to support exercise, and what not.

As I noted, the modern pumps have TWO functions. They have insulin and glucagon. For those who do not know, insulin makes the blood sugar go down, and glucagon makes the blood sugar go up. Neither are secreted by the Pancreas in Type I DM.
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MANF will be much more expensive than this type of system which uses standard compounds and a long lasting delivery system. So, MANF is unlikely to win the competition here.

A treatment is something that has to be given continuously. A cure would involve something that no longer needs to be given. MANF is a treatment and not a cure. Now, Both could be effective cures. That would be a treatment that takes away the complications of the disease 100%, or nearly so. However, MANF will be much more expensive than a bionic pancreas, and so MANF will not win the competition here.

It would be nice to have a cure, for DM. A one and done treatment that led to a cure. That is not on the horizon, let alone on the drawing board.

MANF for the optic Atrophy in WS. Here there is not likely to be any other therapy available for a long time. Like RP, the process is indolent and so MANF could very well work for the Optic Atrophy in WS.

MANF for the CNS signs of WS. If MANF works for this, it will most certainly gain an orphan indication for these patients. This is the primary cause of death in WS patients, and MANF would be used to treat this problem. With 500 patients in the US, there would not be a huge market, but that is the point of the orphan drug system.

Dr Urano and Wolframs


http://wolframsyndrome.blogspot.ch/2014/06/manf-wolfram-and-diabetes-5-protecting.html?spref=tw

1. Inject recombinant MANF to patients.
We can crate MANF in the tissue culture dish using biotechnology. We then purify this "artificial" MANF and use it for the treatment.

2. Stabilize endogenous MANF
There is continuous process of loss and replacement of MANF in our bodies. MANF is degraded after certain amount of time in our cells. If we find a way to stabilize MANF, we can enhance the effect of MANF.

3. Activate a receptor for MANF
Many secreted proteins in our bodies have their "receptors." These receptors mediate the effect of their partner secreted proteins. For example, we have "insulin" receptors to mediate the effect of insulin. We are trying to identify a receptor for MANF, so that we can develop a drug that can activate this receptor.

The next section in this article speaks to the #2 and #3 approaches.
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Session: Late Breaking Poster Session
Abstract Number: 284-LB
Title: A Calcium-dependent Protease As a Potential Therapeutic Target for Wolfram Syndrome, a Prototype of Endoplasmic Reticulum–associated Diabetes
Presentation Start: 6/15/2014 12:00:00 PM
Presentation End: 6/15/2014 2:00:00 PM
Authors: SIMIN LU, KOHSUKE KANEKURA, CHRISTINE M. OSLOWSKI, RITA MARTINEZ, MAYU YAMAZAKI-INOUE, MASASHI TOYODA, AMBER NEILSON, PATRICK BLANNER, CRIS BROWN, JONATHON WASSON, BESS A. MARSHALL, TAMARA HERSHEY, AKIHIRO UMEZAWA, PETER A. GREER, FUMIHIKO URANO, St. Louis, MO, Boston, MA, Tokyo, Japan, Kingston, ON, Canada
Abstract: Endoplasmic reticulum (ER) is an emerging target for human chronic diseases, and Wolfram syndrome characterized by diabetes and neurodegeneration is a prototype of human ER disease. Here we show that the calpain protease is a link between the two Wolfram syndrome genes and death of neurons and ß cells. Calpain activation is mediated by calcium leakage from the ER, which is enhanced by the loss of function of the Wolfram syndrome 1 gene. We show that the Wolfram syndrome 2 gene product (WFS2) associates with and regulates calpain 2. Elevated activation of calpain 2, seen with WFS2 knockdown, correlates with increased death in neurons and ß cells; whereas suppression of calpain 2, seen with over-expression of WFS2, protects these cells from death. Evidence of calpain hyperactivity is observed in a mouse model of Wolfram syndrome as well as in neural progenitor cells derived from induced pluripotent stem cells of patients with Wolfram syndrome. Our results demonstrate that the pathway leading to calpain 2 activation provides potential therapeutic targets for Wolfram syndrome and other ER-associated diseases.
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Calpain 2 is involved here. Dr Urano indicates that it is a target for therapy. #2 and #3 in Dr Urano's plan, could go through Calpain 2 by a variety of mechanisms. Calpain 2 is a protease, and clinicians have attacked proteases before with available technology.
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So this is a potential MANF replacement, or adjuvant. Given that

"the calpain protease is a link between the two Wolfram syndrome genes and death of neurons and ß cells"

They are implying that it is a direct link.

"We show that the Wolfram syndrome 2 gene product (WFS2) associates with and regulates calpain 2. Elevated activation of calpain 2, seen with WFS2 knockdown, correlates with increased death in neurons and ß cells; whereas suppression of calpain 2, seen with over-expression of WFS2, protects these cells from death."

Most certainly they are not talking about MANF and that decreases the market value of MANF. There are more choices out there, and many of them would more than likely be much closer to market
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Note that MANF is involved here. However again, the market only cares about what can get to market first, and MANF remains preclinical. While that will change soon, MANF remains very far away from the clinic.

AMBS ~ "MANF significantly inhibited caspase and calpain-mediated cellular processes of cell death and conferred overall neuroprotection in our cellular model systems of TBI," said Dr. Juan Martinez , Director of Scientific Operations at Banyan Biomarkers. "This neuroprotection indicates therapeutic potential based on well-defined biochemical pathway inhibition. We look forward to working with Amarantus to further develop MANF's therapeutic potential in TBI."

http://www.prnewswire.com/bloggers/news-releases/?nrId=193038121
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It appears that MANF shows up in many processes. These are being elucidated and remain much further off in the future.

Given that acute ischemia may respond to MANF, this is a huge area for future research. Acute ischemia is a common finding in the body. Positive results here would make this a blockbuster. I pick this area over an area that is showing ER stress due to a prion like illness or a genetic defect. (This is very good)
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Lympro

These two links cover the recent developments in Lympro. Taken as a whole, they are not positive and remove Lympro from ANY possibility of revenue any time soon, and probably never. These posts in themselves are long. At some point, I will try to put them into the body of the stickie for better continuity.

The take home is that the accuracy is now 78%, sen 83% spec 73%. Read the links for all of the many details.


http://investorshub.advfn.com/boards/read_msg.aspx?message_id=104345332

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=104345620



1. Before they bought Lympro they had 98 and 95 % sen and spec
2. Results from the Phase 1 study show the scoring model was able to differentiate between AD subjects and other demented subjects (e.g. with PDD or MCI) with co-positivity (sensitivity) up to 91% and co-negativity (specificity) up to 92% relative to the clinical diagnosis of AD.

Between AD subjects and non-AD subjects we found a co-positivity of 88% and a co-negativity of 82%. The separation between AD and OD was particularly apparent, with a SI score at 0.55. This can be seen in the graph below where red bars represent patients with probably AD and the blue bars represent patients with another form of dementia (in this case Parkinson’s disease dementia). The study investigators also found a 95.6% correlation on AUC relative to clinically diagnosed AD compared to OD. Source: Stieler at el; Neurobiology of Aging 33 (2012) 234–241

http://finance.yahoo.com/news/meeting-amarantus-confirms-fundamental-turnaround-160000478.html

This says two things.

a. Lympro could differentiate between AD and other dementias with a sen os 91% and spec of 92%.
b. Lympro was able to differentiate between AD and Non AD with a sensitivity of 88% and a specificity of 82%.

3. In October the company did not release any numbers even though they announced that the test had been verified. This is never done. The sen and spec for that study need to be released before you can judge anything. Not releasing that data, and just SAYING that it is great is totally laughable.

4. The company did just announce that MemoryDx may have come up with a better assay. There are no numbers published yet, and certainly no peer reviewed data.
http://ir.stockpr.com/amarantus/company-news/detail/1254/amarantus-acquires-additional-rights-to-lympro-test-from-memory-dx They are calling this Version 2. During a study, you are supposed to be blinded, so you should not be able to say that the version 2 lympro is going to be better.

Suresh Gupta from Seeking alpha on Lympro

"Assuming Lympro's Phase II success, which would clear the way for CLIA approval and commercialization in 2H2014, investors will have to wait until the completion of Eli Lilly's solanezumab Phase III trial on Autosomal Dominant Alzheimer's patients in December 2016 to see if these asymptomatic patients respond to it, as signified by delay in the disease. If they do, LymPro could prove to be a lot more crucial to the Alzheimer's world than we all thought."

This is a way of saying until there is a treatment for patients who do not have the disease but are destined to get AD, there will be no market for a test given to patients who do not yet have AD. Since this article was written we found out that the Sen and Spec was 81 and 82% for figuring out amongst all comers who would get AD.

now, in that setting, you would actually DO the Lympro and then figure out where Lympro failed so that not all would get treated by doing LPs, PET scans which would take care of things.

However, "investors will have to wait until the completion of Eli Lilly's solanezumab's phase III trial on Autosomal Dominat Alzheimer's patients in December 2016 to see if these assymptomatic patieints respond to it, as signified by a delay in the disease."

And there is absolutely no guarantee that essentially 2017 is the date when Lympro will be used in this very small group of patients. All other treatments for AD have failed, and there are somewhere around 100 compounds that have not worked so far.

Note that these patients have a genetic predisposition to AD ( a rare case ) And so that will decrease the population that gets a lympro test for this reason.

http://seekingalpha.com/article/1773372-amarantus-lympro-may-be-more-crucial-for-alzheimers-treatment-than-we-think

Again, I realize that the SA writer used diplomatic speak, but he DID say that the pertinent study that could result in the use of Lympro will come out in Dec 2016. Essentially 2017.

Again, I would say that is a very generous estimate, and by then the Georgetown test will be close to approval. That is two and a half years away.

Now, GC in his last presentation did note that the company will NOT spend their own money on rolling out Lympro. He also noted that while not in the "Home Stretch" talks on this are close. There were more details in the recent presentation. I put up some notes about that.


Note, like JN, the target of .20 for AMBS by the end of the year, 2014 is repeated by this writer. .20 with a billion shares out there then a 1/25 RS takes you to $5.

That is the data. I say that #1. the .20 is arbitrary, and at around $200 million dollars for a company with no revenue and no clinical studies, is about three times too much in terms of valuation. Remember that JN put on that price target for the end of 2014.

#2, the need for the test, based on the Amvid experience is not as high as you might think.

#3 The consideration that this test will cost $1000 + makes this a pie in the sky effort. In one presentation from last year, GC noted costs would be $70 and priced the test at that time between $300 and $500. Now they want more money for a test that will only do one thing - Tell far too many people who are not going to get AD that they are going to get AD.

Additional data on Lympro from AMBS information from a recent presentation, the data is avail on the ambs site as noted.

Lympro

FDA approval likely 2-­-4 years after CLIA
• International commercialization opportunities:
– Potentially Faster than FDA

page 8
http://content.stockpr.com/amarantus/media/3b975cd360749a34eb202bd4c0121792.pdf
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Now, in the oral presentation and here, they note a retrospective study on Lympro, however it is not retrospective, because they did study these people in 2005, they are doing a follow up. That is not retrospective and makes whatever data obtained possibly more valuable. (Page 15 of the same document )

Retrospective /prognostic 9-­-year patient record clinical study;
• Follow-­-up evaluation of clinical records from patients tested in 2005

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Regarding Eltoprazine

1. The Primary reason this is not a likely candidate for LID Rx is that it makes the PD worse.

2. It did seem to work better for LID when combined with Amantidine in the study. However, Amantidine is the standard, and so you would have to prove that Eltoprazine did something on top of Amantidine to alleviate the LID.

3. Eltoprazine does remain on the MJFF list of potential LID Rx as noted above. If this goes to a trial, I expect MJFF to support it. I do not expect a positive trial because its already been shown to make the PD worse.
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Taking all of this and more in consideration, and looking at comparable companies who have no products and no clinical trials, the market cap should be 60-80 million. I am not a financial analyst. First of all, stocks are worth what folks will pay. Secondly, companies with products in this stage of development are selling for that range. Some commentators have come up with detailed methods of valuing a stock like this. I wonder if that is valid.

Now, PRs are the bread and butter of penny stocks. and so, I would not be surprised to see this stock go to 25 cents.

The stickie posted in 2013 is not significantly different from this one on the matter of MANF in PD, and the overall valuation corrected for events since that time. Things have been added to the post however, which are pertinent. That sticky from 2013 was not meant to be all encompassing. As you know, I've edited this post several times in the last few days. This post will be edited on a prn basis from here on out.

Many parts of this are very technical, if you do not understand part of it, please let me know and I will update the wording. This post is getting panned by many posters. I can only tell you that no compound works for 100% of the indications. That would be called a miracle drug, and we do not have any of those. This is a positive review, and so, after doing your own DD, you can act accordingly.