I do not think so. At present there is non on the market and non of the competing drugs under development do not target this particular mechanism in the first place. But you may find or know one and bring it on this board, please.
My skills to predict a possible partner are non. But this will be a part of all information needed when presenting PBT2 to a partner. Most important studies are clinical studies and I have a lot of hope in the extension study. I think it is important to understand how a drug works and this paper is telling a very essential mechanism about it. Extension study should demonstrate that this mechanism also gives clinically meaningful results, but will it, we do not know yet. Conginition results are difficult to be demonstrated because the lack of placebo group. But IMO the possibilities are better with the hippocampus atrophy rate and also with the PET-scan. However there will be possibilities to look at the relationship between hippocampus atrophy rate and cognition changes. The thing I do not know if any of the used neuropsycholigical test target well enough the function of hippocampus. As you know hippocampus is our GPS device but I has also other functions.
Prof. Masters explaned this mechanism last July in his talk in Copenhagen (slide no 16 in this presentation, can be found on Prana's web page, news reported 17th of July).
This study is very important when in the future treating strokes and brain injuries. To prevent dementia we need to inhibit excitotoxity and the only drug for that is PBT2. Barnham got a grant to do this study, grant was also announced by Prana. Let us see if the good results will be now reported. Hope it will !
Neurobiol Dis. 2015 Feb 17. pii: S0969-9961(15)00028-5. doi: 10.1016/j.nbd.2015.02.008. [Epub ahead of print]
PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning.
Johanssen T1, Suphantarida N2, Donnelly PS3, Liu XM4, Petrou S2, Hill AF5, Barnham KJ6.
Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases. However NMDAR signaling is dichotomous in nature, with excessive increases in neuronal intracellular calcium through excessive NMDAR activity being lethal but moderate increases to intracellular calcium levels during normal synaptic function providing neuroprotection. Subsequently indiscriminant inhibition of this receptor is best avoided as was concluded from previous clinical trials of NMDAR antagonists. We show that the metal chaperone, PBT2, currently in clinical trials for HD, is able to protect against glutamate-induced excitotoxicity mediated through NMDARs. This was achieved by PBT2 inducing Zn2+-dependent increases in intracellular Ca2+ levels resulting in preconditioning of neurons and inhibition of Ca2+-induced neurotoxic signaling cascade involving calpain-activated cleavage of calcineurin. Our study demonstrates that modulating intracellular Ca2+ levels by a zinc ionophore is a valid therapeutic strategy to protect against the effects of excitotoxicity thought to underlie both acute and chronic neurodegenerative diseases.
J Neurosci. 2015 Feb 18;35(7):2871-84. doi: 10.1523/JNEUROSCI.2912-14.2015.
Stabilization of nontoxic aβ-oligomers: insights into the mechanism of action of hydroxyquinolines in Alzheimer's disease.
Ryan TM1, Roberts BR2, McColl G2, Hare DJ3, Doble PA4, Li QX2, Lind M2, Roberts AM2, Mertens HD5, Kirby N5, Pham CL6, Hinds MG7, Adlard PA2, Barnham KJ8, Curtain CC2, Masters CL2.
The extracellular accumulation of amyloid β (Aβ) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aβ, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from Aβ:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aβ fibrillar polymerization and direct depolymerization of existing Aβ fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aβ and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aβ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aβ with an affinity of 1-10 μm and suppress the formation of large ( 30 kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aβ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aβ oligomer formation through stabilization of small (dimeric) nontoxic Aβ conformers.
IMO indefinite does not mean untill extension study results are ready. But it is very natural that during the past 10 months the 1y study results have been analysed even further in the light of other new research of alzheimer's disease ( life style, drugs, exercises, genetics, hippocampus atrophy, PETscan etc). In the summer there was the report by Masters and sure there will be other results when we get the extension study results. I am also sure that a new study plan is on the Prana's table, and published very soon after the extension study results. Now they have ability to do power calculations right after the pilot study.
goutah, I think you have understood it wrong that Alz clinical program would be on indefinite hold. Imagine was only a small pilot study to give advice for future studies, what to measure etc. In the next few weeks the extension study results are ready and they together with 1y results will determine how to go forward. What needs to be controlled in the future as perhaps ApoE4, BDNF, diet, other medicines, life style etc. And now there is also the problem of dossage. Only now there is enough info (?) to plan a good ph3 study when the extension study results are ready.
How to get safer dosage ?? I understand that FDA will help in this but I Shoulson will also have some knowledge in this. Now it was 250mg a day and this is not enough for Prana anymore. What I remember the half-life of PBT2 is about 15h (???) . My trick would be to give 200mg twice or 150mg 3 times and with these the max consentration in the tissue would be almost same as 250mg will cause, perhaps little more but the total dosage would be 60% or 80% higher than it was in the HD study. Slow releasing tablet would be even better.
An other issue is to have a longer study. 6 months is a very short time to demonstrate in MRI the atrophy rate reduction of brain. In this respect there is eveidence that some 35-40 patients are needed in each study group if the treatment time is 1y and you expect to see 50% reduction.
The solutions to the problems presented today can be very simple, but these were only my immediate thoughts. There will be some simple solutions FDA and Prana can agree.
goutah, perhaps i do not understand well enough this "petri dish" model, but to me it is self clear that PBT2 does not need that kind of an experiment at this phase. "petri dish " is perhaps a tool to test all other MPACs but PBT2 needs now testing in humans: amyloid levels, cognition, hippocampus and brain atrophy measures etc. These cannot be seen or measured on a Petri dish. The corresponding experiment to petri dish was what Susan Lindquist did with her yeast model few years ago. It is perhaps more likely thatTanzi could test weather his petri dish will give same results what Prana will get now in the extension study, positive or negative. Prana needs now Mr. Lawler's results and all other ones in the extension study. Those results are possibly the best booster for the pps, if they are positive as I do believe.
Biotech invest, I recommend you to read the old paper by Bush: An iron-export ferroxidase activity of β-amyloid protein precursor is inhibited by zinc in Alzheimer’s Disease. It is a free paper published in Cell.
Modulation of tau phosphorylation by environmental copper.
Voss K1, Harris C1, Ralle M2, Duffy M2, Murchison C1, Quinn JF3.
The transition metal copper enhances amyloid β aggregation and neurotoxicity, and in models of concomitant amyloid and tau pathology, copper also promotes tau aggregation. Since it is not clear if the effects of environmental copper upon tau pathology are dependent on the presence of pathological amyloid β, we tested the effects of copper overload and complexing in disease models which lack pathological amyloid β.
We used cell culture and transgenic murine models to test the effects of environmental copper on tau phosphorylation. We used oral zinc acetate as a copper lowering agent in mice and examined changes in blood and brain metals through inductively coupled plasma mass spectroscopy. Behavioral effects of copper lowering were assessed with Morris water maze and novel object recognition tasks. Changes in tau phosphorylation were examined by phosphorylation specific antibodies on Western blots.
In human neuroblastoma cells, excess copper promoted tau phosphorylation and a copper complexing agent, tetrathiomolybdate, attenuated tau phosphorylation. In a transgenic mouse model expressing wild type human tau, copper-lowering by oral zinc suppressed plasma and brain levels of copper, and resulted in a marked attenuation of tau phosphorylation. No significant changes in behavior were observed with copper lowering, but a trend to improved recognition of the novel object was observed in zinc acetate treated mice.
We propose that reduction of brain copper by blocking uptake of copper from the diet may be a viable strategy for modulating tau pathology in Alzheimer's disease. The potential benefits of this approach are tempered by the absence of a behavioral benefit and by the health risks of excessive lowering of copper.
The same authors published 1 y ago
The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders.
Urrutia PJ1, Mena NP1, Núñez MT1.
A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich's ataxia and Parkinson's disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson's disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.
It is a free paper in the net.
Perhaps Prana has not been thinking this indication before. I would guess that the problem is not only iron but also some other metals, metal balance is disturbed (??).