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Prana Biotechnology Limited Message Board

  • pivalde pivalde Feb 3, 2013 7:45 AM Flag

    Misfolding protein diseases, big target for Prana

    AD, HD and PD are typical misfolding protein diseases, but there are many others as indicated in the abstract by Cao & Kaufmann, Jan 17, 2013 below. Prana has over 800 MPACs to test but already now we know that PBT2 will lengthen the life of experimental animals, perhaps helping in those pathologies Cao and Kaufman tell us.

    Introduction: Endoplasmic reticulum (ER) stress, a condition that dramatically affects protein folding homeostasis in cells, has been associated with a number of metabolic diseases. Emerging preclinical and clinical evidence supports the notion that pharmacological modulators of ER stress have therapeutic potential as novel treatments of metabolic disorders. Areas covered: In this review, the molecular mechanisms of ER stress and the unfolded protein response (UPR) in the pathogenesis of metabolic diseases are discussed, highlighting the roles of various UPR components revealed using disease models in mice. Special emphasis is placed on the use of novel small molecules in animal disease models and human pathologies, including type 2 diabetes, obesity, fatty liver disease, and atherosclerosis. Expert opinion: ER stress is a highly promising therapeutic target for metabolic disease. Small molecular chemical chaperones have already demonstrated therapeutic efficacy in animal and human studies. The emergence of compounds that target specific UPR signaling pathways will provide more options for this purpose. Although the findings are promising, more studies are needed to elucidate the efficacy and side effects of these small molecules for future use in humans.

    Sentiment: Strong Buy

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    • Many remember that clioquinol was originally used as a very good diarrhoea drug. Chronic colitis seems to be also a misfolding protein disease as indicated in the abstract below. So when you look at the diseases Prana's MPACs could one day work, the list is very long. Not only neurodegenerative diseases but also diabetes, obesity, liver diseases, atherosclerosis, colitis, may be rheumatic diseases etc.
      Here is the colitis abstract by Cao et al, also published in last month. You only need to think that the chaperones mentioned can be replaced by one of Prana's 800 MPACs and that this study is also only an animal study but at the same time we know that the original clioquinol was a very good drug in treating chronic diarrhoea in humans.
      BACKGROUND & AIMS:

      Endoplasmic reticulum (ER) stress has been associated with development of inflammatory bowel disease (IBD). We examined the effects of ER stress-induced chaperone response and the orally active, chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylbutyrate (PBA), which facilitate protein folding and reduce ER stress, in mice with colitis.

      METHODS:

      We used dextran sulfate sodium (DSS) to induce colitis in mice that do not express the transcription factor ATF6a or the protein chaperone P58IPK. We examined the effects of TUDCA and PBA in cultured intestinal epithelial cells (IECs), in wild-type, P58IPK-/-, and Atf6a-/- mice with colitis, and in Il10-/- mice.

      RESULTS:

      P58IPK-/-, and Atf6a-/- mice developed more severe colitis following administration of DSS than wild-type mice. IECs from P58IPK-/- mice had excessive ER stress, and apoptotic signaling was activated in IECs from Atf6a-/- mice. Inflammatory stimuli induced ER stress signals in cultured IECs, which were reduced by incubation with TUDCA or PBA. Oral administration of either PBA or TUDCA reduced features of DSS-induced acute and chronic colitis in wild-type mice, the colitis that develops in Il10-/- mice, and DSS-induced colitis in P58IPK-/-, and Atf6a-/- mice. Reduced signs of colonic inflammation in these mice were associated with significantly decreased ER stress in colonic epithelial cells.

      CONCLUSIONS:

      The unfolded protein response induces expression of genes that encode chaperones involved in ER protein folding; these factors prevent induction of colitis in mice. Chemical chaperones such as TUDCA and PBA alleviate different forms of colitis in mice and might be developed for treatment of inflammatory bowel diseases.

      Sentiment: Strong Buy

      • 1 Reply to pivalde
      • The misfolding protein diseases is getting more and more interest.

        This abstract below in from Lancet neurology by Roussel BD et al, Jan 2013.

        "Endoplasmic reticulum (ER) dysfunction might have an important part to play in a range of neurological disorders, including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases, and familial encephalopathy with neuroserpin inclusion bodies. Protein misfolding in the ER initiates the well studied unfolded protein response in energy-starved neurons during stroke, which is relevant to the toxic effects of reperfusion. The toxic peptide amyloid β induces ER stress in Alzheimer's disease, which leads to activation of similar pathways, whereas the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood ER-overload response. In other neurological disorders, such as Parkinson's and Huntington's diseases, ER dysfunction is well recognised but the mechanisms by which it contributes to pathogenesis remain unclear. By targeting components of these signalling responses, amelioration of their toxic effects and so the treatment of a range of neurodegenerative disorders might become possible".

        All these diseases are very difficult to treat if there is any treatment at all. If PBT2 will now work in AD aswell as in HD, there will be huge interest in similar type of drugs (as what Prana has already some 800 of them waiting in it's library) to find a treatment for these other diseases Prana has not yet done any research. As some of you know Gammagard from Baxter seems to work just in endoplasmatic reticulum and is the only other drug than PBT2 demonstrated efficacy in AD.

        Sentiment: Strong Buy

 
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