Saturday, April 6, 2013

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

 

Scientists Identify First Potentially Effective Therapy for Human Prion Disease





By Eric Sauter





Human diseases caused by misfolded proteins known as prions are some of most rare yet terrifying on the planet—incurable with disturbing symptoms that include dementia, personality shifts, hallucinations and coordination problems. The most well-known of these is Creutzfeldt-Jakob disease, which can be described as the naturally occurring human equivalent of mad cow disease.




Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time identified a pair of drugs already approved for human use that show anti-prion activity and, for one of them, great promise in treating these universally fatal disorders.




The study, led by TSRI Professor Corinne Lasmézas and performed in collaboration with TSRI Professor Emeritus Charles Weissmann and Director of Lead Identification Peter Hodder, was published this week online ahead of print by the journal Proceedings of the National Academy of Sciences.




The new study used an innovative high-throughput screening technique to uncover compounds that decrease the amount of the normal form of the prion protein (PrP, which becomes distorted by the disease) at the cell surface. The scientists found two compounds that reduced PrP on cell surfaces by approximately 70 percent in the screening and follow up tests.




The two compounds are already marketed as the drugs tacrolimus and astemizole.




Tacrolimus is an immune suppressant widely used in organ transplantation. Tacrolimus could prove problematic as an anti-prion drug, however, because of issues including possible neurotoxicity.




However, astemizole is an antihistamine that has potential for use as an anti-prion drug. While withdrawn voluntarily from the U.S. over-the-counter market in 1999 because of rare cardiac arrhythmias when used in high doses, it has been available in generic form in more than 30 countries and has a well-established safety profile. Astemizole not only crosses the blood-brain barrier, but works effectively at a relatively low concentration.




Lasmézas noted that astemizole appears to stimulate autophagy, the process by which cells eliminate unwanted components. “Autophagy is involved in several protein misfolding neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases,” she said. “So future studies on the mode of action of astemizole may uncover potentially new therapeutic targets for prion diseases and similar disorders.”




The study noted that eliminating cell surface PrP expression could also be a potentially new approach to treat Alzheimer’s disease, which is characterized by the build-up of amyloid β plaque in the brain. PrP is a cell surface receptor for Aβ peptides and helps mediate a number of critical deleterious processes in animal models of the disease.




The first author of the study, “Unique Drug Screening Approach for Prion Diseases Identifies Tacrolimus and Astemizole as Antiprion Agents,” is Yervand Eduard Karapetyan of The Scripps Research Institute. Other authors include Gian Franco Sferrazza, Minghai Zhou, Gregory Ottenberg, Timothy Spicer, Peter Chase, Mohammad Fallahi, Peter Hodder and Charles Weissmann of The Scripps Research Institute. For more information on the study, see




http://www.pnas.org/content/early/2013/03/29/1303510110.abstract





The research was supported by The Scripps Research Institute, the Alafi Foundation and the National Institutes of Health (Grant MH084512).


 


 
Send comments to: mikaono@scripps.edu






http://www.scripps.edu/newsandviews/e_20130408/lasmezas.html







Sent: Thursday, April 04, 2013 5:04 PM
Subject: Re: [BSE-L] Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

Abstract

Prion diseases such as Creutzfeldt–Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP–FRET-enabled high throughput assay (PrP–FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identifiedastemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the blood–brain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform.

Footnotes

  • 1Y.E.K. and G.F.S. contributed equally to this work.
  • 2Present address: Oncological Dispensary, Histopathology, Stepanakert, Nagorno-Karabakh Republic, 375000 Azerbaijan.
  • 3Present address: OPKO Health Inc., Diagnostic Research, Jupiter, FL 33458.
  • 4To whom correspondence may be addressed. E-mail: lasmezas@scripps.edu or charlesw@scripps.edu.
  • Author contributions: P.H., C.W., and C.I.L. designed research; Y.E.K., G.F.S., M.Z., G.O., T.S., and P.C. performed research; Y.E.K., G.F.S., M.Z., G.O., T.S., P.C., M.F., P.H., C.W., and C.I.L. analyzed data; and C.I.L. wrote the paper.
  • The authors declare no conflict of interest.
  • This article contains supporting information online at
  •  


      http://www.pnas.org/content/early/2013/03/29/1303510110.abstract?sid=ccdac972-b912-4d19-8ba0-48399d33eeee






      Воскресенье, 31 марта 2013, 11:35 -05:00 от "Terry S. Singeltary Sr." :

      Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray
      'Pray por Cristina' video highlights prayer movement for girl with degenerative disease
      Date: 2013-03-31 08:00:00
      March 31, 2013. (ROMEREPORTS.COM) (-VIDEO ONLY-) A social network that allows users to ask and give prayers, MayFeelings.com, published the story of one of its youngest members. Her name is Cristina and is the youngest person in the world that suffers from a degenerative neurological disease called Creutzfeldt-Jakob, a fatal condition that attacks the brain.
      Her parents have tried all they can to try to save her, but no known cure of the disease has been developed. As a result, his father Juan Perican uploaded her story to the social network, which has drawn support from thousands throughout the world.
      Using the hashtag #prayporcristina on Twitter, they ask for prayers. “People call us asking if we need anything, money, if they could help us... but we only want to be with Cristina. We thank them a lot of their support, but we always tell them the same thing: the only thing they can do is pray,” her mother explains in the video.
       
       
       
      sporadic CJD, 11 year old victim, 2 year clinical course to date ???
      Saturday, March 23, 2013
      CJD Incidents Panel to be disbanded
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      16 YEAR OLD SPORADIC FFI ?
      Monday, January 14, 2013
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      Monday, December 31, 2012
      Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State, 2006–2011-2012
      Tuesday, December 25, 2012
      CREUTZFELDT JAKOB TSE PRION DISEASE HUMANS END OF YEAR REVIEW DECEMBER 25, 2012
      Tuesday, June 26, 2012
      Creutzfeldt Jakob Disease Human TSE report update North America, Canada, Mexico, and USDA PRION UNIT as of May 18, 2012
      type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the rise in Canada and the USA
      Wednesday, June 13, 2012
      MEXICO IS UNDER or MIS DIAGNOSING CREUTZFELDT JAKOB DISEASE AND OTHER PRION DISEASE SOME WITH POSSIBLE nvCJD
      *** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
      VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion poker goes up again $
      OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles
      Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve University; Cleveland, OH USA
      Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.
      Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.
      Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases.
      In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.
      Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.
      The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
      Wednesday, March 28, 2012
      VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion poker goes up again $
      Tuesday, March 5, 2013
      Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)
      FDA believes current regulation protects the public from BSE but reopens comment period due to new studies
      Tuesday, March 05, 2013
      A closer look at prion strains Characterization and important implications Prion
      7:2, 99–108; March/April 2013; © 2013 Landes Bioscience
      Wednesday, March 20, 2013
      GAO-13-244, Mar 18, 2013 Dietary Supplements FDA May Have Opportunities to Expand Its Use of Reported Health Problems to Oversee Product
      From: Terry S. Singeltary Sr.
      Sent: Tuesday, March 19, 2013 2:46 PM
      To: gomezj@gao.gov
      Cc: siggerudk@gao.gov ; youngc1@gao.gov ; wlmailhtml:sentmsg?mailto=mailto%3aoighotline@gao.gov
      Wednesday, February 20, 2013
      World Organization for Animal Health Recommends United States' BSE Risk Status Be Upgraded
      Statement from Agriculture Secretary Tom Vilsack:
      Thursday, February 14, 2013
      The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease
      TSS
      Sunday, March 31, 2013
      Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray



      Yervand Karapetyan
      Post-Graduate student
      Department of Pathology
      Yerevan State Medical University
      Koryun str, 2
      Yerevan 375025
      Republic of Armenia
      tel: 003741 268131
      fax: 003741 527284
      email:yervandkar@yahoo.com

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