Experimental treatments for human TSE (prion)

Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion

2011-08-01T11:14:00.001-07:00

Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion

Hiroyuki Honda1,*, Kensuke Sasaki1, Haruhiko Minaki1, Kenta Masui1, Satoshi O. Suzuki1, Katsumi Doh-ura2, Toru Iwaki1Article first published online: 1 AUG 2011

DOI: 10.1111/j.1440-1789.2011.01245.x

© 2011 Japanese Society of Neuropathology

Keywords:Creutzfeldt-Jakob disease;oligomer;pentosan polysulfate;prion protein;size-exclusion gel chromatography

Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrPres) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3–10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrPres in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrPres was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.

http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1789.2011.01245.x/abstract

Tuesday, June 14, 2011

sporadic CJD, Quinacrine Study, MRI misdiagnosis USA

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/clinical-research-in-cjd-at-us-clinical.html

http://prionpps.blogspot.com/2011/06/sporadic-cjd-quinacrine-study-mri.html

Thursday, October 15, 2009

ANA: No Benefit for Quinacrine in CJD

http://prionpps.blogspot.com/2009/10/ana-no-benefit-for-quinacrine-in-cjd.html

Wednesday, March 11, 2009

PRION1 trial reports quinacrine does not increase survival in patients with prion disease

http://prionpps.blogspot.com/2009/03/prion1-trial-reports-quinacrine-does.html

Wednesday, March 26, 2008

Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK

http://prionpps.blogspot.com/2008/03/intraventricular-pentosan-polysulphate.html

UPDATE JULY 2011 MORE OF THE "PENDING CLASSIFICATION CREUTZFELDT JAKOB DISEASE'' STEADY INCREASING...TSS

case; 5 Includes 13 cases in which the diagnosis is pending, and 18 inconclusive cases; 6 Includes 18 (15 from 2011) cases with type determination pending in which the diagnosis of vCJD has been excluded.

http://www.cjdsurveillance.com/pdf/case-table.pdf

Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)

http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html

Saturday, March 5, 2011

MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/mad-cow-atypical-cjd-prion-tse-cases.html

Wednesday, March 31, 2010

Atypical BSE in Cattle

To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE.

When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.

This study will contribute to a correct definition of specified risk material (SRM) in atypical BSE. The incumbent of this position will develop new and transfer existing, ultra-sensitive methods for the detection of atypical BSE in tissue of experimentally infected cattle.

http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2

Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.

***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat

snip...

http://www.neuroprion.org/en/np-neuroprion.html

http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html

http://prionpathy.blogspot.com/

Rural and Regional Affairs and Transport References Committee

The possible impacts and consequences for public health, trade and agriculture of the Government's decision to relax import restrictions on beef Final report June 2010

2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric, epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey told the committee of his concerns regarding the lengthy incubation period for transmissible spongiform encephalopathies, the inadequacy of current tests and the limited nature of our current understanding of this group of diseases.49

2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50

http://www.aph.gov.au/senate/committee/rrat_ctte/mad_cows/report/report.pdf

14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

T. Singeltary

Bacliff, TX, USA

Background:

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

Methods:

12 years independent research of available data

Results:

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

Conclusion:

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf

Monday, May 23, 2011

Atypical Prion Diseases in Humans and Animals 2011

Top Curr Chem (2011)

DOI: 10.1007/128_2011_161

# Springer-Verlag Berlin Heidelberg 2011

Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar

Abstract

Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.

M.A. Tranulis (*)

Norwegian School of Veterinary Science, Oslo, Norway

e-mail: Michael.Tranulis@nvh.no

S.L. Benestad

Norwegian Veterinary Institute, Oslo, Norway

T. Baron

Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France

H. Kretzschmar

Ludwig-Maximilians University of Munich, Munich, Germany

Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type

http://resources.metapress.com/pdf-preview.axd?code=f433r34h34ugg617&size=largest

snip...SEE MORE HERE ;

http://bse-atypical.blogspot.com/2011/05/atypical-prion-diseases-in-humans-and.html

Tuesday, April 26, 2011

sporadic CJD RISING Text and figures of the latest annual report of the NCJDRSU covering the period 1990-2009 (published 11th March 2011)

http://creutzfeldt-jakob-disease.blogspot.com/2011/04/sporadic-cjd-rising-text-and-figures-of.html

Wednesday, June 29, 2011

TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products

http://tseac.blogspot.com/2011/06/tseac-meeting-august-1-2011-donor.html

Friday, June 17, 2011

Treatable neurological disorders misdiagnosed as Creutzfeldt-Jakob disease

http://creutzfeldt-jakob-disease.blogspot.com/2011/06/treatable-neurological-disorders.html

Saturday, January 22, 2011

Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/alzheimers-prion-and-neurological.html

Wednesday, July 20, 2011

Canadian Researchers Receive $2.9 Million to Protect Against Prion Disease Outbreaks, Develop Novel Therapies to Treat Alzheimer's, Parkinson's and ALS

http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/canadian-researchers-receive-29-million.html

http://bse-atypical.blogspot.com/

http://chronic-wasting-disease.blogspot.com/

http://nor-98.blogspot.com/

http://scrapie-usa.blogspot.com/

http://transmissible-mink-encephalopathy.blogspot.com/

http://creutzfeldt-jakob-disease.blogspot.com/

http://sporadicffi.blogspot.com/

http://kuru-tse.blogspot.com/

http://prionopathy.blogspot.com/

http://transmissiblespongiformencephalopathy.blogspot.com/

TSS

sporadic CJD, Quinacrine Study, MRI misdiagnosis USA

2011-06-14T08:39:00.000-07:00

Tuesday, June 14, 2011

Clinical research in CJD at a U.S. clinical prion research center: CJD Quinacrine Study results and improved diagnosis of prion disease

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/clinical-research-in-cjd-at-us-clinical.html

ANA: No Benefit for Quinacrine in CJD

2009-10-15T14:03:00.000-07:00

ANA: No Benefit for Quinacrine in CJD

By Richard Robinson, Contributing Writer, MedPage Today Published: October 15, 2009 Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit for reading medical news

Action Points --------------------------------------------------------------------------------

¦Explain to interested patients that sporadic CJD is a progressive brain disease due to accumulation and spread of misfolded protein.

¦Explain that the drug quinacrine did not extend survival in patients with CJD despite its ability to eliminate prions in vitro.

¦Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

BALTIMORE -- The first U.S. treatment trial for sporadic Creutzfeldt-Jakob disease (CJD) has shown that quinacrine does not extend survival compared with placebo, a researcher reported here.

Nonetheless, the trial represents progress in understanding the natural history of CJD and provides researchers with a prototype for future trials, according to lead investigator Michael Geschwind, MD, PhD, Assistant Professor of Neurology at the University of California San Francisco, and a researcher at the Memory and Aging Center there.

Geschwind described the study at the annual meeting of the American Neurological Association.

CJD is a prion disease, caused by accumulation of misfolded prion proteins in neurons: the misfolded proteins then cause others to misfold, spreading the pathology.

A small percentage of CJD cases are due to mutation in the prion gene, but most cases are sporadic. There are approximately 300 new cases of sporadic CJD in the U.S. every year. It is rapidly progressive, with few patients surviving more than a year after onset.

Quinacrine is an antimalarial drug that can eliminate prions in cell cultures. Open-label treatment in a handful of patients seemed to suggest a benefit for survival, so Geschwind developed a protocol for a blinded trial.

"We struggled with whether it was ethical to do a placebo-controlled trial in a uniformly fatal disease, but really that's the only way we are going to get the correct answer," Geschwind said. Using historical controls was not an option, because there was too much variability among samples.

Fifty-four patients with confirmed sporadic CJD were randomized to either quinacrine or placebo for two months, after which they could elect to switch to open-label quinacrine. The main outcome measure was survival from randomization, with follow-up at months two, six, and 12.

"Unfortunately, there was no survival difference between the two groups, either at two months or over the course of the disease," he said.

But the trial nonetheless produced important results. "It was not a complete loss. We know we can do a trial in a rapidly progressive, fatal disease. We now have very quantifiable data on natural history, so when the next drug becomes available, we'll be able to do a trial very quickly. And I am confident we will find more compounds."

For effective therapy, Geschwind said, "We are probably going to need more than one drug -- one to help clearance, one to prevent conversion of normal to abnormal protein, and perhaps even one to diminish the level of normal protein itself, so there is less substrate for the abnormal protein. We and other labs are screening compounds for these effects."

Geschwind reported no financial conflicts. The study was funded by the National Institutes of Health.

Primary source: American Neurological Association Source reference: Geschwind MD, et al "The first U.S. treatment trial for sporadic CJD" ANA 2009; Abstract T-71.

http://www.medpagetoday.com/Neurology/GeneralNeurology/16447

http://www.neuroprion.org/en/video_090711_10.html

View of NCT00183092 on 2009_03_10 ClinicalTrials Identifier: NCT00183092 Updated: 2009_03_10 Descriptive Information Brief title CJD (Creutzfeldt-Jakob Disease) Quinacrine Study

Official title Novel Therapeutics For Prion Diseases: A Randomized, Double-Blinded, Placebo-Controlled Study of the Efficacy of Quinacrine in the Treatment of Sporadic Creutzfeldt-Jakob Disease

Brief summary The purpose of this clinical trial is to determine the effectiveness of the medication quinacrine on survival in sporadic Creutzfeldt-Jakob disease (sCJD).

Detailed description Creutzfeldt-Jakob disease (CJD)is a rapidly progressive, invariably fatal and untreatable neurodegenerative disease with a mean duration of about eight months. Beyond the debilitating cognitive and motor deficits that accompany CJD, the difficulty in treating behavioral and mood disturbances and the rapidity of its course compound its tragedy. Recent results from experiments show that, at physiological concentrations, the anti-malarial drug quinacrine permanently clears abnormal prion proteins from cell culture. The demonstrated efficacy of quinacrine in cell culture, its relative safety and well known side-effects in the clinical setting, and the universal fatality of CJD justify quinacrine as an immediate candidate for the treatment of CJD.

The purpose of this clinical trial is to determine the efficacy of the medication quinacrine on survival in sporadic CJD (sCJD). This will be accomplished by bringing approximately 60 patients with probable or definite sCJD over approximately three years to UCSF for evaluation and initiation of a randomized, double-blinded, placebo-controlled (delayed treatment start) treatment study of quinacrine. Each patient will have a 50:50 chance of being placed on quinacrine or placebo upon study enrollment; however, all patients will be offered quinacrine after two months. Prior to study enrollment, patients will have a comprehensive clinical assessment to confirm the diagnosis of sCJD. Participants will come to UCSF for initial evaluation, potential study enrollment and, if possible, return to UCSF for follow-up at two and twelve months. Patients will receive telephone follow-up (every 2 weeks for the first two months and monthly thereafter) and local blood and testing to monitor for possible medication toxicity.

Phase Phase 2 Study type Interventional Study design Treatment Study design Randomized Study design Double Blind Study design Placebo Control Study design Parallel Assignment Study design Efficacy Study Primary outcome Survival from the time of randomization Secondary outcome Scores on functional scales, neurological exam and functional testing Condition Creutzfeldt-Jakob Disease Intervention Drug: Quinacrine

Reference Citation: Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83. Review. MEDLINE: 9811807 Reference Citation: Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9836-41. MEDLINE: 11504948 Reference Citation: Scoazec JY, Krolak-Salmon P, Casez O, Besson G, Thobois S, Kopp N, Perret-Liaudet A, Streichenberger N. Quinacrine-induced cytolytic hepatitis in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2003 Apr;53(4):546-7. No abstract available. MEDLINE: 12666126 Reference Citation: Wallace DJ. Is there a role for quinacrine (Atabrine) in the new millennium? Lupus. 2000;9(2):81-2. No abstract available. MEDLINE: 10787002 Reference Citation: Engel GL. Quinacrine effects on the central nervous system. JAMA. 1966 Aug 8;197(6):515. No abstract available. MEDLINE: 5952734

URL

http://memory.ucsf.edu

URL

http://ind.universityofcalifornia.edu/

See also UCSF Memory & Aging Center

See also UCSF Institute for Neurodegenerative Diseases

Recruitment Information Status Active, not recruiting Start date 2005-04 Criteria Inclusion Criteria: - Diagnosis of probable or definite sCJD: Definite--biopsy confirmed sCJD; Probable--a progressive dementia with either a typical EEG or a typical MRI consistent with sCJD, and at least two of the following clinical features: myoclonus, pyramidal or extrapyramidal signs, visual symptoms, cerebellar signs, akinetic mutism, other focal higher cortical neurologic signs (e.g. neglect, apraxia, aphasia) - 18 years of age or older - Able to swallow - Able to follow simple one-step commands - Have had a brain MRI within 6 months and an EEG within 3 months ruling out other etiologies such as masses, strokes, or non-convulsive status epilepticus - Consent to autopsy in the event of their death during or after the study

Exclusion Criteria: - History of other significant or life-threatening disease, including: cancer; end-stage liver or renal disease; severe heart disease - History of other disease requiring regular supportive care - Liver disease - Active alcoholism - Bone marrow suppression - Severe hypotension - Severe psoriasis - Poorly controlled diabetes - Women who are pregnant or breast-feeding - Men, or women of childbearing age, not practicing reliable contraception - Serious allergies to quinacrine or other acridines - Current or recent use of quinacrine (within 6 months) - < 18 years of age - Any other contraindication to taking quinacrine - Genetic form of prion disease is identified prior to study enrollment - Current use of anti-arrhythmics (at discretion of investigator) - G6PD (Glucose 6-Phosphate Dehydrogenase) deficiency (at discretion of investigator)

Gender Both Minimum age 18 Years Healthy volunteers No Administrative Data Organization name National Institute on Aging (NIA) Organization study ID IA0083 Secondary ID AG21601-03 Lead sponsor National Institute on Aging (NIA) Health Authority United States: Food and Drug Administration

http://clinicaltrials.gov/archive/NCT00183092/2009_03_10

http://clinicaltrials.gov/show/NCT00183092

Saturday, June 13, 2009

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009

http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html

Tuesday, August 11, 2009

Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants

Brian S. Appleby, MD; Kristin K. Appleby, MD; Barbara J. Crain, MD, PhD; Chiadi U. Onyike, MD, MHS; Mitchell T. Wallin, MD, MPH; Peter V. Rabins, MD, MPH

Background: The classic Creutzfeldt-Jakob disease (CJD), Heidenhain, and Oppenheimer-Brownell variants are sporadic CJD (sCJD) phenotypes frequently described in the literature, but many cases present with neuropsychiatric symptoms, suggesting that there may be additional sCJD phenotypes.

Objective: To characterize clinical, diagnostic, and molecular features of 5 sCJD variants.

Design: Retrospective analysis.

Setting: The Johns Hopkins and Veterans Administration health care systems.

Participants: Eighty-eight patients with definite or probable sCJD.

Main Outcome Measures: Differences in age at onset, illness progression, diagnostic test results, and molecular subtype.

Results: The age at onset differed among sCJD variants (P=.03); the affective variant had the youngest mean age at onset (59.7 years). Survival time (P.001) and the time to clinical presentation (P=.003) differed among groups. Patients with the classic CJD phenotype had the shortest median survival time from symptom onset (66 days) and those who met criteria for the affective sCJD variant had the longest (421 days) and presented to clinicians significantly later (median time from onset to presentation, 92 days; P=.004). Cerebrospinal fluid analyses were positive for 14-3-3 protein in all of the affective variants, regardless of illness duration. Periodic sharp-wave complexes were not detected on any of the electroencephalography tracings in the Oppenheimer-Brownell group; basal ganglia hyperintensity was not detected on brain magnetic resonance imaging in this group either. All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

Conclusions: The classic CJD phenotype and the Heidenhain, Oppenheimer-Brownell, cognitive, and affective sCJD variants differ by age at disease onset, survival time, and diagnostic test results. Characteristics of these 5 phenotypes are provided to facilitate further clinicopathologic investigation that may lead to more reliable and timely diagnoses of sCJD.

Arch Neurol. 2009;66(2):208-215

snip...

COMMENT

snip...see full text ;

http://creutzfeldt-jakob-disease.blogspot.com/2009/08/characteristics-of-established-and.html

Thursday, September 24, 2009

Suit: Meatpacker used `downer' cows for 4 years TO FEED OUT CHILDREN ALL ACROSS THE NATION, the most high risk for mad cow disease

http://downercattle.blogspot.com/2009/09/suit-meatpacker-used-downer-cows-for-4.html

Monday, May 11, 2009

Rare BSE mutation raises concerns over risks to public health

http://bse-atypical.blogspot.com/2009/05/rare-bse-mutation-raises-concerns-over.html

TSS

PRION1 trial reports quinacrine does not increase survival in patients with prion disease

2009-03-11T12:36:00.000-07:00

PRION1 trial reports quinacrine does not increase survival in patients with prion disease

10 March 2009

The drug quinacrine does not increase survival in patients with prion diseases including variant Creutzfeldt-Jakob Disease (vCJD). The finding comes from evidence collected during the PRION-1 trial, the first clinical trial of a potential treatment for human prion diseases in the UK. The results are published in Lancet Neurology.

Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), can arise spontaneously, be inherited through a genetic mutation, or develop through infectious transmission. The most common form is sporadic CJD, which affects about one to two people in a million worldwide every year. The neurodegenerative disorders caused by prion disease are fatal and progress rapidly. Currently, there are no therapeutic interventions that prevent or reverse progression in human prion diseases.

The Chief Medical Officer for England asked the Medical Research Council to prepare a protocol for a clinical trial in human prion disease to investigate quinacrine’s therapeutic potential, activity and safety. There are no other drugs currently available which are considered suitable for human evaluation. PRION-1 was led by Professor John Collinge, Director of the MRC Prion Unit, and was funded by the MRC and Department of Health.

Quinacrine (Mepacrine), a drug used to treat malaria and some arthritic illnesses, has been shown to be effective in treating prion-infected cells in the laboratory, by blocking the conversion of normal prion proteins into the abnormal disease-causing form. Oral quinacrine is also known to be safe and well-tolerated in humans and can cross the difficult blood-brain barrier. Interest in this potential treatment grew, and some patients requested immediate access to quinacrine.

A formal consultation process with patients, families, carers and representatives of patients was undertaken to develop an acceptable study design to assess the efficacy and safety of oral quinacrine in all forms of prion disease in the UK.

Patients in the PRION-1 trial were offered the choice of quinacrine, no quinacrine, or to be randomly assigned to receive quinacrine either immediately or after a delay. In total 107 patients with prion disease were recruited to the trial from across the UK using a national referral system. Of these people, 45 had sporadic prion disease, two had iatrogenic (acquired from a hospital procedure), 18 had variant CJD and 42 had inherited prion disease. Patients were eligible if they had any form of prion disease and were more than 12 years old. Neurological assessments and clinical investigations were carried out at the start of the study, again after one, two, four and six months, and then at regular intervals of three months.

Only two of 84 patients, or their carers where the individuals did not have the capacity to make the decision themselves, agreed to randomisation. This means that PRION-1 was primarily an observational study of patients who did or did not choose quinacrine. The authors identified disease severity as a strong determinant of this choice, with those least and most severely affected least likely to choose the drug.

In total, 78 patients died—one randomly assigned to deferred treatment, 26 of 38 who took the drug immediately, and 51 of 69 who initially chose no quinacrine. Mortality was lower in patients who chose to take quinacrine than in those who did not, but after adjusting for confounding factors such as disease severity and type of disease there was no difference in survival significant enough to suggest quinacrine is a successful treatment option.

Importantly, the authors believe that although the study demonstrated that national recruitment and retention to trials of treatment of prion disease is both feasible and acceptable to patients and carers, it highlighted the difficulty of conducting randomised controlled trials. Patients who have a fatal disease that progresses rapidly often want whatever potential treatment is available. This means they are reluctant to be randomised to a deferred treatment option. Similarly when a patient has advanced disease, families are not prepared to accept an intervention that is expected to merely slow or halt disease progression.

The authors conclude that earlier diagnosis must be: ‘‘A high priority if patients are to be included in treatment trials, as those with mild to moderate disease are probably most likely to accept randomisation, and likely to benefit most from any effective treatment.”

Original research paper: Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial is published in Lancet Neurology 2009; 8: 334–44.

Press contact: 020 7637 6011 mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000555/!x-usc:mailto:press.office@headoffice.mrc.ac.uk

http://www.mrc.ac.uk/Newspublications/News/MRC005691

Experimental treatments for human TSE (prion)

http://prionpps.blogspot.com/

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Father’s relief at £3m vCJD victims study

2009-02-11T10:41:00.001-08:00

Father’s relief at £3m vCJD victims study

3:50pm Wednesday 11th February 2009

Holly Mills with her mum, Linda, and dog, Jack, at Dalby Forest

By Mike Laycock »

HOLLY MILLS has survived for more than five years since doctors diagnosed her as suffering from the devastating illness variant CJD – and warned that she had only weeks to live.

Her father, Peter, convinced the 23-year-old is only alive today because of a revolutionary treatment she has been given since 2003, has been pressing for years for research into the drug, pentosan polysulphate (PPS).

Now Mr Mills, of Thornton-le-Dale, near Pickering, has told of his relief after being informed that the Department of Health has finally ordered a £3 million study into all types of vCJD (Creutzfeldt-Jakob disease) and its treatment.

He said he had been asked to sit on an oversight group for the cohort study, which was set to be launched next month and would be led by Professor John Collinge, of the National Prion Unit at the National Hospital for Neurology and Neurosurgery in London.

Mr Mills said the study was the breakthrough he and his wife, Linda, had been hoping for ever since October 2003, when Holly became one of the first people in the world to have PPS pumped directly into their brain.

Holly, who had previously been fit and healthy, fell ill when she was 17. Her parents do not know why she caught vCJD, although they suspect it may have been through eating contaminated beef products more than two decades ago.

The Mills went public on Holly’s condition in 2005 – lifting a High Court ban on her identification – so they could demand research into the drug and its effects on the illness.

Mr Mills said today her condition had remained stable over the years since the treatment started, with her weight remaining constant, and he and Linda believed she had continued to show slight, but significant improvements.

She could make oral noises to communicate with them and used an exercise bike daily, albeit strapped safely into position. Mr Mills said: “It’s not dramatic, but we are hoping that one day, within five years, diagnostics and treatment will be devised that can reverse her illness.”

Neuological expert Ian Bone conducted a study of several patients receiving PPS treatment on behalf of the Medical Research Council (MRC) in 2005.

An MRC report said afterwards PPS was a molecule derived from beech wood which had many properties such as blood thinning, and it was licensed to treat bladder inflammation.

Prof Bone said some of the patients treated with PPS appeared to have survived for long periods, but it could not be concluded the treatment had a beneficial effect, because it was impossible to make direct comparisons with similar, but untreated patients.

Rare disease research

THE Department of Health has confirmed it will fund a three-year, £3 million National Prion Monitoring Cohort study through its Policy Research Programme.

A spokesman said human prion disease remained very rare, but it was possible that the numbers of people affected by variant CJD – the prion disease linked to BSE – might increase.

He said an extensive research programme was seeking to promote early diagnosis and develop treatments for such diseases.

“We have conducted the first clinical trial for prion disease in the UK. We are now launching the National Prion Monitoring Cohort study,” he said.

This observational cohort study would collect data on all patients diagnosed with, or at high risk of developing prion disease, regardless of whether or not they were receiving treatment, and would monitor changes in the progression of the disease during their natural history or in response to therapeutic and other interventions.

http://www.thepress.co.uk/news/4116854.Father___s_relief_at___3m_vCJD_victims_study/

Experimental treatments for human TSE (prion)

http://prionpps.blogspot.com/

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Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion

2008-07-19T10:14:00.000-07:00

Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion

disease Melanie D. White*, Michael Farmer, Ilaria Mirabile, Sebastian Brandner, John Collinge, and Giovanna R. Mallucci† Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom Edited by Charles Weissmann, The Scripps Research Institute, Jupiter, FL, and approved June 3, 2008 (received for review March 19, 2008)

Prion diseases are fatal neurodegenerative conditions for which there is no effective treatment. Prion propagation involves the conversion of cellular prion protein, PrPC, to its conformational isomer, PrPSc, which accumulates in disease. Here, we show effective therapeutic knockdown of PrPC expression using RNAi in mice with established prion disease.Asingle administration of lentivirus expressing a shRNA targeting PrP into each hippocampus of mice with established prion disease significantly prolonged survival time. Treated animals lived 19% and 24% longer than mice given an ‘‘empty’’ lentivirus, or not treated, respectively. Lentivirally mediated RNAi of PrP also prevented the onset of behavioral deficits associated with early prion disease, reduced spongiform degeneration, and protected against neuronal loss. In contrast, mice receiving empty virus or no treatment developed early cognitive impairment and showed severe spongiosis and neuronal loss. The focal use of RNAi therapeutically in prion disease further supports strategies depleting PrPC, which we previously established to be a valid target for prion-based treatments. This approach can now be used to define the temporal, quantitative, and regional requirements for PrP knockdown for effective treatment of prion disease and to explore mechanisms involved in predegenerative neuronal dysfunction and its rescue.

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Discussion The rescue of early neuronal dysfunction before neuronal loss is established is a clear goal for therapeutic intervention in neurodegenerative disease. Our previous findings that transgene-mediated PrP knockdown reversed predegenerative pathological changes and early behavioral deficits in prion disease led us to try to achieve the same effect therapeutically. PrPC knockout, both during development and postnatally, appears to be without detrimental effect (6, 21). We used RNAi to silence PrP expression in mice with established prion disease. Knockdown of PrP by RNAi (11) and resultant inhibition of PrPSc replication in cell culture have been described (12), and RNAi of PrP also works in vivo. Transgenic mice generated by lentiviral transduction of embryos stably express anti-PrP shRNAs and have increased resistance to prion infection because of RNAi-mediated reduced expression of endogenous PrP (13). However, until now, RNAi had not been used therapeutically in vivo in prion disease. Here, we have shown that treating mice with lentiviruses expressing shRNAs to knockdown PrP in established prion disease rescued early neuronal dysfunction and death in targeted areas and significantly prolonged survival. Injection of virus into the hippocampus 8 weeks after prion infection prevented the first behavioral deficits associated with early pathology of the CA1 region: loss of burrowing activity and object recognition memory (22) (Fig. 2). In our previous work, where PrP knockdown was due to recombination at the genomic level at 8 wpi, early deficits occurred but recovered rapidly in PrP-depleted animals. Here, injection of lentivirus expressing anti-PrP shRNAs at 8 wpi prevented their manifestation altogether, perhaps because posttranscriptional gene silencing is more rapid, or more tightly controlled temporally, than genetic excision of PrP encoding sequences after transgene expression. The benefits of RNAi treatment were also seen morphologically. There was significantly less spongiform degeneration and neuronal loss where anti-PrP lentivirus was delivered. These changes progress rapidly in RML-infected tg37 mice after 8 wpi, particularly in the hippocampus (4), and were marked in terminally ill LV-

Empty-treated animals at 12 wpi (Fig. 4). However, LV-MW1- treated mice culled up to 3 weeks later had minimal hippocampal spongiform change and neuronal loss (Fig. 4), suggesting sustained focal protection against neurotoxicity where PrP knockdown occurred. Interestingly, spongiosis was also reduced, although less significantly, in thalamus and cortex of animals treated with hippocampal injections (Fig. 5). PrPSc accumulation was also lower in animals with virally mediated RNAi of PrP in the hippocampus than in mock treated animals, and again this reduction was seen beyond the hippocampus, in thalamus and cortex. The more widespread changes are likely to reflect altered spread of prion infection after hippocampal PrP knockdown, as discussed below. Of note, PrPSc accumulation did not appear to affect neuronal function or survival, as reflected in preservation of hippocampal behaviors and structural neuronal integrity, and consistent with our observations in mice with Cre-mediated PrP depletion (5), which has implications for the level of knockdown required for therapeutic effect. Thus, simply slowing the rate of prion replication, here by reducing PrPC levels, may be effective for prevention of neurotoxic effects. The critical effect, however, was the effect of this treatment on survival of prion-infected mice. A single treatment with focal injection of virus resulted in significantly prolonged survival time of treated animals, compared with mock or untreated mice, with a mean increase in lifespan of 23.5% compared with untreated animals (Fig. 3). The spread of incubation times in the LV-MW1 group (87–129 days after inoculation, mean 105 4 days) is probably due to variation in neuronal transduction by virus seen in individual mice (data not shown) or variability between individual injections, with the highest levels of transduction affording the greatest protection and longest survival. The increased survival was strikingly large with respect to the very small volume of brain targeted. This may result from direct or indirect effects of localized neuroprotection or may simply be due to the reduction of PrP expression at a critical, or rate-limiting, site for prion replication. Prion incubation times are known to be inversely proportional to overall levels of PrP expression (3, 23, 24), and it is likely that regional variations also affect prion replication rates and incubation periods. The hippocampus is a focus of early prion replication and PrPSc deposition (see Fig. S3) both forRMLand other prion strains in various inbred lines and in some transgenic mice (25, 26), including tg37 mice, used here (4). We showed up to 80% reduction of hippocampal PrP mRNA expression (Fig. 1B) with single LV-MW1 administration; this localized knockdown may therefore eliminate a key area for early prion replication in this model. Further, we have found no evidence for the spread of lentivirus beyond the injection site, supporting the concept that it is the effect of localized hippocampal PrP depletion that alters the spread and replication of RML prions in this model. Clearly, all animals succumb eventually, presumably due to prion-mediated neurodegeneration in other critical brain regions, but the neuroprotective effects seen within the hippocampus and beyond are clearly a desirable effect of therapy. If transduction were to be more widespread, by pseudotyping lentiviruses with coat proteins that allow retrograde transport (27, 28) or using evolving mechanical techniques for enhanced delivery (29–31), more extensive neuroprotection and longer survival might ensue. Even focal targeting may have therapeutic application in some situations, however. In conclusion, we have used lentivirally mediated RNAi for treatment of established prion infection in mice. Even localized single administration of these viruses to the hippocampus prolonged the lifespan of infected mice, protected transduced neurons from degenerating, reduced PrPSc accumulation, and prevented the onset of the first behavioral deficits associated with the disease. Our findings urther support therapeutic strategies directed at PrP knockdown for the treatment of prion diseases and are also relevant for neurodegeneration more widely, highlighting the importance of intervention when neuronal dysfunction can still be reversed. The approach used here paves the way not only for possible future therapy but also for mechanistic dissection of toxicity and recovery in prion diseases. Further exploration of the extent and timing of RNAi-mediated PrP knockdown required for increased therapeutic effect in prion disease can now be undertaken. Methods...snip...end

White et al. PNAS July 22, 2008 vol. 105 no. 29 10243 NEUROSCIENCE

www.pnas.orgcgidoi10.1073pnas.0802759105

Author contributions: G.R.M. designed research; M.D.W., M.F., I.M., and S.B. performed research; M.D.W., M.F., I.M., S.B., J.C., and G.R.M. analyzed data; and G.R.M. wrote the paper. Conflict of interest statement: J.C. is a director and shareholder of D-Gen Limited, an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics. D-Gen markets the ICSM35 and ICS18 antibodies used in this study. This article is a PNAS Direct Submission. Freely available online through the PNAS open access option. *Present address: Centre for Neuroscience Research, University of Edinburgh, EH8 9XD, United Kingdom. †To whom correspondence should be addressed. E-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000004/!x-usc:mailto:g.mallucci@prion.ucl.ac.uk. This article contains supporting information online at www.pnas.org/cgi/content/full/ 0802759105/DCSupplemental. © 2008 by The National Academy of Sciences of the USA

full text ;

http://www.pnas.org/content/early/2008/07/15/0802759105.full.pdf+html

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Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK

2008-03-26T11:24:00.000-07:00

To cite this article: I. Bone, L. Belton, A. S. Walker, J. Darbyshire (2008)

Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK

doi:10.1111/j.1468-1331.2008.02108.x

Abstract

Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK

I. BoneaaDepartment of Medical and Cardiovascular Studies, Western Infirmary, Glasgow, UK, L. BeltonbbMRC Clinical Trials Unit, London, UK, A. S. WalkerbbMRC Clinical Trials Unit, London, UK and J. DarbyshirebbMRC Clinical Trials Unit, London, UKaDepartment of Medical and Cardiovascular Studies, Western Infirmary, Glasgow, UK and bMRC Clinical Trials Unit, London, UK Prof. Ian Bone, Department of Medical and Cardiovascular Studies, Western Infirmary, Glasgow G11 6NT, UK (tel.: 44 1436 671472 e-mail: gcl136@clinmed.gla.ac.uk).

Abstract

Background and purpose: This observational study assessed the effect of continuous intraventricular infusion of pentosan polysulphate (PPS) in seven patients at different clinical centres in the UK.

Methods and results: Complications of intraventricular catheterization were frequent. PPS was well-tolerated over a wide dose range (11–110 µg/kg/day) during the 6-month study. Four patients were assessed for the entire study period: one remained stable, two showed minimal deterioration and one progressed significantly. Mean survival of all patients was longer than reported values for natural history of specific prion disorders.

Conclusion: Possible reasons for these findings are explored.

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Disease duration and survival

Survival of the seven patients from estimated disease onset to death or last known alive (see clinical assessment section) is documented in Table 1. Table 2 compares data for seven patients plus the extra case [14] with those of natural history patients. Individual survival of all patients in all disease groups (16–75 months) was at or beyond the reported means [20] and medians [M. Pocchiari, personal communication; 21]. All but one vCJD patient also survived beyond the ranges of survival determined by both Pocchiari (personal communication) and Stewart et al. [21].

Other investigations

Patients underwent various tests, including coagulation, electrolyte and cerebrospinal fluid protein 14-3-3 levels, differential cell counts, erythrocyte sedimentation rate, urinalysis, chest X-rays, analysis of gait, heart rate variability and detailed neuropsychometry. All had initial CT scans, and some had further CT/MRI monitoring (between 1 and 18 scans per patient). Sequential scans (Fig. 4) were carried out in only three patients.

Discussion

PPS was administered by the intraventricular route and complications with the catheterization procedure occurred in four of seven patients, as previously observed [14,15]. Some catheters were positioned biventricular and some univentricular, though substances

injected into just one ventricle may distribute evenly throughout the CNS [22,23]. The extent of PPS distribution will be critical, given the diffuse pathology of the different prion disorders [24,25].

No safe or effective dosing regimen has been established for PPS in humans. Doses varied 10-fold in this study. The dose of 11 lg/kg/day, derived from animal studies [10] and calculated from total body area [14], may be an underestimate for infusion into a single compartment (M. Rawlins, personal communication). Doses up to 110 lg/kg/day were tolerated, with no toxicity, increase in seizures or haemorrhagic complications. The low patient numbers made conclusions of safety unreliable – only overt toxicity could be detected.

Standardized follow-up imaging, which might have allowed crude assessment of brain atrophy [26], was not performed regularly in these patients (not at all in one) [26]. Assessment was further confounded by movement artefacts. Sequential scans were rarely taken, but did reveal continuing atrophy throughout therapy (Fig. 4). Frisoni et al. [27] emphasize the need for prospective imaging to assess brain atrophy, preferably at a single site and with movement artefacts minimized. Of the four patients assessed prospectively for the entire 6-month study, one remained stable, two showed minimal deterioration and one deteriorated signifi- cantly. PPS efficacy was difficult to quantify because of the short time frame, low patient numbers, variable patient/disease characteristics and differences in management and assessment. It was not possible to recruit a control group with matching baseline features as planned in the initial protocol.

Survival, as measured by the interval between disease onset and death, can be a robust end-point for measuring efficacy. However, it is very difficult to establish retrospectively when the first symptoms emerged. Increased public awareness of these diseases and differences in the ability to identify/recall details of early nonspecific symptoms may mean that diagnosis is being made earlier in the disease course. Comparisons with previous data may, therefore, be subject to lead-time bias. Even if the precise point of onset can be determined, disease survival is probably to be influenced by age and gender, genotype, disease-modifying treatments, level of care, treatment complications, infections, immobility and nutritional status. A collaborative study [20] used data from 10 national registries of prion disorders, including untreated (natural history) cases, and revealed differences in survival in vCJD, iatrogenic (human growth hormone) and inherited (GSS) forms of the disease (Table 2). Additional survival data were provided by Stewart et al. [21] in a systematic review that included studies showing variability in disease progression, levels of care, lifeending decisions and life-prolonging interventions. Table 2 compares the survival of the seven patients with published figures [M. Pocchiari, personal communication; 21].

There are many possible reasons why survival of PPS-treated patients might appear longer compared with such untreated patients: including chance alone and biases such as lead-time bias from attentive carers diagnosing onset early; selection bias from included patients having prolonged survival whilst awaiting PPS or bias from increased use of active interventions for complications in more actively managed PPS patients amongst others. Self-selection related to longer survival is less probably in this study because there were variable delays from disease onset to treatment (4–19 months in vCJD cases; 7–11 months in iatrogenic cases and 29– 43 months in GSS cases).

Survival of all seven patients exceeded mean survival of natural history patients [20] but were within reported ranges for iatrogenic and inherited cases [21]. Three out of four vCJD patients (including the additional patient

from [14]) survived longer than the reported median and range for both natural history studies [M. Pocchiari, personal communication; 21]. By definition, for every new patient surviving longer than the median survival time, one will not – thus the probability of surviving longer than the median survival time is 0.5. If there were no effect of PPS on survival, the probability of two patients with iatrogenic or inherited prion disease both exceeding the median survival time of previous untreated patients just by chance is 0.25 (0.52). The probability of four vCJD patients exceeding the median survival time by chance alone is 0.0625 (0.54). Compared with natural history data [M. Pocchiari, personal communication; 21], the patients with inherited GSS had survival times of 52 and 64 months (last seen alive), which lie within reported range [21] for untreated patients and thus do not differ significantly. The two patients with iatrogenic disease died 29 and 32 months after diagnosis, both similar to the maximum reported by Stewart et al. [21]. Rank-sum testing suggests the probability of two treated patients surviving beyond the maximum of 111 untreated patients (if there were no difference between treated and untreated patients and also none of the other potential biases described above) is 0.02, which indicates there may be a very weak suggestion/ possibility of some effect given the fact that survival times were similar to the maximum, and the strong possibility of lead-time bias in this group of patients. Of the four vCJD patients, in whom untreated comparison patients are more contemporaneous, one survived for 16 months (beyond the median of 13 months in (M. Pocchiari, personal communication) and 14 months in [21]) and three are still alive in August 2007 (all exceeding the mean, median and range of untreated patients in both natural history studies). The probability of this occurring (if there were no difference between the treated and natural history patients and no other potential biases) is 0.01, indicating some suggestion/ possibility of an effect.

These findings must, of course, be interpreted cautiously because of the difficulty in determining disease onset from non-specific and subtle symptoms and the very small numbers. An accurate date of onset and a longer period of prospective assessment would yield more data for evaluating efficacy. However, if other explanations can be discounted, then prolonged survival in these patients may suggest a treatment effect of PPS.

Conclusions

This small case series found that widely varying doses of PPS delivered intraventricularly were safe, resulting in patient survival similar to or greater than in previously reported historical controls, in most cases. However, complications from the surgical procedures were common. Small observational studies with this much variability cannot quantify efficacy and offer only limited data on safety. They can, however, be valuable if procedural and follow-up protocols are strictly controlled. Recent draft guidelines on clinical trials in small populations by the Committee for Medicinal Products for Human Use recognize the importance of observational studies and case reports when data are collected in a controlled manner. They recommend use of a surrogate marker when recruitment of sufficient patients is difficult or will take a very long time. This commonly occurs in studies of the rare human prion diseases, yet there are no obvious surrogate markers. More experimental work in animal models is clearly needed, both on efficacy and on the distribution and binding of PPS following intraventricular administration. If results are encouraging, a controlled trial in human prion disease should be considered, having determined optimum doses. Until then, all patients with prion diseases considering PPS therapy should be informed of existing evidence and, if opting for treatment, managed and monitored in a standardized manner.

Acknowledgements

We thank the patients and families who participated in this study and the UK PPS-treating clinicians (UK PPS Treating Clinicians: J. Bamford, Leeds; A. Gale, London; P. Newman, Middlesbrough; C. Rickards, Swansea; S. Wimalaratna, Swindon) and Maria Hampshire for her help in manuscript preparation. This study was proposed by the Department of Health and funded by the UK Medical Research Council.

http://www.blackwell-synergy.com/doi/abs/10.1111/j.1468-1331.2008.02108.x

PAST HISTORY ON PPS AND OTHER TREATMENTS FOR HUMAN TSE

Subject: Findings of MRC monitoring study of Pentosan Polysulphate treatment in CJD patients does not stop the progression of vCJD and other prion diseases

Date: July 12, 2006 at 10:29 am PST

##################### Bovine Spongiform Encephalopathy #####################

Findings of MRC monitoring study of PPS (does not stop vCJD) Wed Jul 12, 2006 12:18 68.238.98.70

12 Jul: Pentosan Polysulphate & CJD

Findings of MRC monitoring study of Pentosan Polysulphate treatment in CJD patients

A Medical Research Council monitoring study of a small number of UK patients has found that a compound called Pentosan Polysulphate (PPS) does not stop the progression of vCJD and other prion diseases but the report recommends more research. The study provides qualified reassurance on some of the safety concerns that have been raised previously. The observational study of seven patients was carried out by Professor Ian Bone from Glasgow, Intraventricular Pentosan Polysulphate in Human Prion Diseases: A study of Experience in the United Kingdom, is a summary of the responses that people with prion diseases have shown to PPS.

The chemical nature of PPS means that it is unable to enter the brain if administered orally or intravenously. For the purposes of this treatment, therefore, it has been administered directly into the ventricles of each patient’s brain - a route known as intraventricular delivery. Fluid circulating around the brain from the ventricles potentially provides a route to spread PPS around the brain tissue.

Professor Bone carried out the study based on analysis of seven patients’ treatment and he stresses that the findings should not be taken as conclusive, because the report was based on a very small number of patients, treated in different ways, and because like-with-like comparisons with untreated patients were not possible. However any severe side-effects or clear benefit of PPS treatment in halting progression could have been revealed by this study. The findings are being made available now, to inform the debate over this treatment.

The MRC’s New Therapies Scrutiny Group endorsed the recommendations of Professor Bone’s report:

Further experimental work in animals will provide the most immediate source of evidence of whether or not PPS is likely to extend survival. We need better information on the extent to which PPS penetrates and spreads through the infected brain. The Medical Research Council will take this forward. Further clinical research could be undertaken. Ideally, a formal prospective longitudinal standardised follow-up study would be required but this must be dependent on the results of the experimental animal work being encouraging. In the meantime, newly diagnosed patients should be informed verbally and in writing about current knowledge of PPS, including the risks associated with intraventricular catheterisation, when treatment options are discussed. The Medical Research Council will take forward this recommendation with the Department of Health. Informed people opting for intraventricular PPS should undergo the procedure to fit the catheter and pump at a neurosurgical centre with appropriate experience of such surgery. However, dose initiation and escalation could be managed locally. People treated in this manner should be followed up through an approved protocol of clinical assessments and investigations. Current patients on PPS should continue to be monitored as part of a supportive, structured review, and should be given up to date information and advice. Professor Bone said: “Pentosan Polysulphate itself does not seem to carry a high probability of side effects from prolonged usage. However, the surgical complications of intraventricular catheter and pump placement were significant. The drug does not appear to halt the progression of the disease. Loss of brain function continues after treatment has started and, where measured by imaging, loss of brain tissue also continued. This is the first time that this mode of drug delivery has been carried out over such a prolonged period of time. The study shows that intraventricular delivery might provide a long-term alternative route for other future therapies that cannot enter the nervous system by oral or intravenous routes in situations where the surgical risks are justified.”

He went on: “The patients treated with PPS appear to have survived for unusually long periods. However, we cannot conclude with certainty that the treatment has a beneficial effect, because it was impossible to make direct comparison with similar but untreated patients. Moreover, with such small numbers the results might be a matter of chance. The report recommends specific laboratory experiments to address the uncertainties.”

Professor Ian Bone said “I am very grateful to the families and patients who participated in the study, and I hope that my report will help people who have to take difficult decisions about treatment in future. A report like this cannot always offer definite answers, and we urgently need further rigorous research to give scientists, doctors, patients and their families more information on which to base future treatment decisions.”

The co-chair of the committee, Professor Sir Michael Rawlins welcomed the study: “Professor Bone’s observations have helped cast light on a little known and difficult-to-research area. He has shown that Pentosan Polysulphate itself does not appear toxic at the modest doses given and leaves open the intriguing possibility that it may have some effect on the duration of survival. Sadly it seems that a loss of brain function continues in patients being treated with PPS. Professor Bone has also confirmed what we knew at the outset – that the surgical procedure needed to administer PPS carries a degree of risk, though is generally considered to be acceptable given the advanced stage of the disease in these patients. The recommendation that surgery be carried out in an experienced centre, and to an approved protocol, should help reduce complications associated with the surgery.”

Lester Firkins, the other co-chair, added: “This is a very important report which will inform current and future patients and their families – and also our collective knowledge of this tragic disease. I am very pleased that the MRC New Therapies Scrutiny Group agreed to advise MRC to carry out further research as a matter of urgency to fill in the gaps in the knowledge on PPS. Additionally, it should now be possible to help new patients and their families with better information on the risks of PPS by the publication of a balanced information leaflet. We are all indebted to the current patients and their families for participating in this study – and of course they must continue to benefit from appropriate monitoring and support.”

If you would like to arrange an interview please contact the MRC press office on 020 7637 6011 press.office@headoffice.mrc.ac.uk

Notes for editors:

MRC New Therapies Scrutiny Group for Prion Disease

The MRC New Therapies Scrutiny Group for Prion Disease (NTSG) was established in 2005 at the request of the Chief Medical Officer (CMO), to provide an independent source of advice on research into the development of potential therapeutics or preventative agents for prion disease. NTSG will build upon the previous work of the Department of Health CJD Therapy Advisory Group (TAG).

NTSG reports to the Medical Research Council (and other bodies when appropriate). The Group will advise MRC on the development of new therapeutic agents that could possibly be brought to bear upon this disease and will also maintain an overview of other relevant research.

The Medical Research Council

The Medical Research Council (MRC) is funded by the UK tax-payer. It aims to improve human health. The research it supports and the scientists it trains meet the needs of the health services, the pharmaceutical and other health-related industries and universities. The MRC has funded work which has led to some of the most significant discoveries and achievements in medicine in the UK.

©2006 Medical Research Council

http://www.mrc.ac.uk/index/public-interest/public-news_centre/public-press_office/public-press_2006/public-press_12_july_2006.htm

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APPROACHES TO THERAPY OF PRION DISEASES

CharlesWeissmann1 and Adriano Aguzzi2

1Department of Neurodegenerative Disease/MRC Prion Unit, Institute of Neurology,

Queen Square, London WC1N 3BG, United Kingdom;

email: charles.weissmann@prion.ucl.ac.uk

2Institute of Neuropathology, University Hospital, CH-8091 Z¨urich, Switzerland;

email: adriano@pathol.unizh.ch

Key Words transmissible spongiform encephalopathies, Creutzfeldt-Jakob

disease, bovine spongiform encephalopathy, proteinopathy, neuroblastoma cells

¦ Abstract

Devising approaches to the therapy of transmissible spongiform encephalopathies, or prion diseases, is beset by many difficulties. For one, the nature of the infectious agent, the prion, is understood only in outline, and its composition, structure, and mode of replication are still shrouded in mystery. In addition, the mechanism of pathogenesis is not well understood. Because clinical disease affects mainly the brain parenchyme, therapeutic agents must be able to traverse the brain-blood barrier (BBB) or have to be introduced directly into the cerebrospinal fluid or brain tissue. And finally, because the disease is usually recognized only after onset of severe clinical symptoms, the question arises as to whether the neurodegenerative processes can be reversed to any extent after a successful eradication of the agent.

THE DISEASE

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PRION DISEASE THERAPY 335

ATTEMPTS AT HUMAN THERAPY

The earliest attempts to treat human prion disease, performed when the agent was generally assumed to be a virus, were carried out with antiviral drugs, such as amantadine, and were unsuccessful (137).

Quinacrine

Quinacrine, chlorpromazine, and some tricyclic derivatives with an aliphatic side chain were described as efficient inhibitors of PrPSc formation in murine neuroblastoma cells chronically infected with the Chandler scrapie isolate (138, 139). Because quinacrine and chlorpromazine have been used in human medicine as antimalarial and antipsychotic drugs, respectively, and because they cross the BBB, they were proposed as therapeutic agents for CJD patients (139). No therapeutic effectwas seen following quinacrine treatment of 20 patients (140) (A. Alperovich, quoted in Reference 141), although some transient improvement occasionally occurred (142). Subsequent animal experiments failed to demonstrate efficacy in the treatment of TSEs (141), even after intraventricular infusion (135).

Amphothericin B

Amphothericin B and some of its analogues delayed the appearance of spongiosis, astrogliosis, and PrPSc accumulation in the brain of scrapie-infected hamsters (125). However, an attempt to treat a CJD patient with amphothericin B was unsuccessful (143). In view of its high systemic toxicity, these results dampen any hopes that amphothericin B will prove useful in prion disease therapy.

Pentosan Polysulfate

Data presented at two prion meetings in 2002, and published recently (135), suggest that intraventricular administration of PPS to intracerebrally prion-infected mice prolonged incubation time. PPS is marketed in some countries as a treatment for interstitial cystitis and as an anticoagulant, although its side effects include hemorrhage and hypersensitivity reactions.

ETHICAL CONSIDERATIONS

Recently a legal case was brought by two families whose children JS and PA, aged 18 and 16 respectively, suffered from vCJD [DS v JS and an NHS Trust and The Secretary of State for Health, intervenor; PA v JA and an NHS Trust and The Secretary of State for Health (2002) EWHC 2734 (Fam)]. They applied to the court to permit intraventricular administration of PPS, a treatment previously given only to rodents and dogs. The judge heard testimony from Doh-Ura, the Japanese researcher who had performed the animal studies; from a neurosurgeon

336 WEISSMANN AGUZZI

willing to administer the novel treatment; and from several respected neurologists who expressed reservations about it. The judge found that both young patients had “some enjoyment from life which is worth preserving” and that the treatment, as it was supported by medical opinion, would be in their “best interest” (the legal criterion for doctors to treat patients who lack capacity for personal decisions) (144). Treatment has been initiated, but no reports on the fate of the patients have been issued.

Physicians can thus come under pressure from the courts to allow new treatments to be used without having been tested in clinical trials, although the ruling described above implies that such decisions would have to withstand the “Bolam” test of being acceptable to a reasonable body of medical opinion. The ruling also upheld the application of the Human Rights Act in this area, citing Articles 2 and 8, the rights to life and to respect for family life. It is not inconceivable that such analysis could allow patients to circumvent clinical trials by asserting their rights to receive innovative therapy, and this development is of concern, particularly in the clinical field of human prion diseases.

We may at some stage be confronted with a therapy that can eradicate prion infection without reversing the neural damage, which in extreme cases could condemn patients to years or decades of severe disability and dementia. This would lead to an ethical dilemma as to whether treatment should be withheld if the disease has progressed to a severe stage. Such situations could be prevented if a diagnostic test could detect prion disease in its preclinical stage. Whether such a test, if it ever became available, would be applied to detect a disease with an incidence of 1 in a million per year is a matter of debate; clearly it would be practicable in the case of familial prion diseases.

The Annual Review of Medicine is online at

http://med.annualreviews.org/

LITERATURE CITED...snip...end...tss

Benefits

It is possible that this treatment will slow (or even halt) progression of disease but there is no guarantee and no present means of objectively quantifying the degree of possibility. Any such effect, IF it were to occur would probably be temporary. It is not possible to give any indication of any time limit on such an effect. The possibility that any such effect could continue throughout the duration of treatment cannot be absolutely excluded but it seems unlikely. Clearly, the later in the disease process that such a treatment were to be undertaken, the less likely any benefit would be seen. Also, in late stages of disease, slowing of progression might be difficult to objectively assess. There are, currently, no validated laboratory or imaging assessments that could be used to give unequivocal evidence of efficacy; one would have to rely on more subjective assessments including everyday functional ability and serial neurological impairment examinations, perhaps with the adjunct of neuropsychological assessments. However, research is being undertaken to see if certain tests could be useful in monitoring disease progression.

On the basis of current understanding, there is no realistic possibility of actual improvement in the sense of reversal of previously established neurological deficit. Again, this cannot be absolutely excluded but it seems highly improbable, especially in relatively late stages of disease.

To date, at least several human individuals with prion disease have been treated with intraventricular PPS. There are also families who have considered the treatment and decided that they do not wish for it. There are no hard data currently in the public domain. However, one individual (with vCJD) is said to have not shown any clear evidence of deterioration over a period of at least 23 months (as at February 2005). The person concerned was at a late stage of illness at the time of treatment, with very significant neurological impairment and it could be difficult to assess any signs of deterioration or minor improvement in this sort of situation. This period of apparent clinical stability could be taken as evidence that this treatment has indeed had a beneficial effect in this one individual. However, some individuals with prion diseases go through 'plateau' periods and, to some extent, survival in the later stages of illness depends on the level and quality of general nursing care provided . The present duration of apparent clinical stability must at least suggest the possibility of some treatment efficacy. In addition, there have been suggestions of minor clinical improvements. However, at present, it cannot be stated that this one treated individual provides definite evidence of efficacy of intraventricular PPS. No information is currently available on the other treated individuals.

The best possible outcome from intraventricular PPS

On the basis of the available evidence, the best possible outcome that could be expected after treatment with intraventricular PPS is that there may be some temporary slowing or halting of the disease progression. However, there is little likelihood of significant clinical improvement. Nor is there a likelihood of permanent halting of disease progression. Of course, to some extent, this might depend on the duration of intraventricular PPS administration. It is not clear on what basis one would decide on the duration of treatment.

Naturally, a treatment which stabilises an individual's condition could conceivably lead to an individual being in a state of potential suffering for a longer period of time. It might be proposed that any slowing of progression or halting of progression might allow an individual to survive longer and therefore receive future more beneficial treatment if it were to become available. However, this would be a speculative view and, while treatments for CJD are being researched, there is no realistic expectation of a complete cure in the immediate future.

Additional Comments

Any conclusion concerning these above considerations, in the context of an individual person, would necessarily involve a number of very difficult or personal judgements about quality of life and the degree of suffering experienced by an individual in a disease like CJD. Any such judgements are bound to be subjective and reflect both general belief systems and personal evaluations of the individual patient. There are clearly important issues of consent and also issues as to the full understanding of those involved as to the potential benefits and risks. Clearly, there are few hard data on which to make clear decisions. At this point, the human treatment data do not allow for any specific comments which can be made concerning problems or benefits, aside from the facts that there are no reported major serious complications and that there has been no obvious clinical deterioration over some months of treatment in at least one case.

Any decision about a given patient would have to be taken in an entirely individual way, based on a detailed assessment of both the patient and the concerned relatives. The overriding principle should be: What is in the best interests of the individual patient? bearing in mind that CJD is inevitably and invariably a progressive and fatal disease.

There is, of course, an argument that such treatment should be evaluated in the context of a properly organised clinical trial. There are no current plans to set up such a trial and, in relation to this specific issue, the comments of two relevant professional bodies (given in the section below) should be noted.

Advice from relevant professional bodies

The Department of Health have statements on intraventricular PPS on their website:

www.doh.gov.uk/cjd/pentosan_revised.htm

This includes statements of advice from the CJD Therapy Advisory Group and the CSM.

The advice from the CJD Therapy Advisory Group can be summarised as follows:

There are insufficient clinical data to support the claim that PPS is effective during clinical disease.

There are insufficient safety data on which to base a rational treatment regimen in humans.

Further animal model experimental work is warranted.

Nevertheless, at the dosage used in at least one individual, there have been no definite harmful effects attributable to the drug.

All patients with prion disease should undergo appropriate monitoring during disease progression, in a way that allows collection of data on the natural history of disease and on any treatments that might be given.

The advice from the CSM is similar and states further that:

"there is no evidence in support of its use as a treatment in late stage disease".

"In the light of the limited information on PPS treatment of clinically established vCJD it is impossible to assess the risk/benefit relationship of PPS in these indications".

There was insufficient information to reach any conclusions about the efficacy of treatment in [the single case known about at the time of the statement].

They also recommended that further study of PPS should be undertaken in a clinical trial setting.

Neither of these statements preclude the possibility of an individual clinician deciding to treat an individual patient; such decisions remain absolutely individual ones. However, clinicians would wish to consider any such decisions in the light of all the available information and advice.

The case of the first individual who received this treatment was referred to the High Court and there was a ruling in favour of this particular individual being allowed to receive such treatment, as being in that individual's overall best interests. However, this was an individual ruling relating to a particular individual. It is understood that other cases have been referred to court, but again on an individual basis.

There are important issues of consent regarding such 'experimental' treatment, both with regard to the age of some affected individuals and also with regard to competence (where disease affects the brain).

The Department of Health has sought to identify certain selected hospitals where IVPPS treatment might be instituted, if there is a strong desire for it by a family and agreement by their relevant clinician, so as to centralise any experience with this treatment. Such centres will develop protocols for the referral of patients and the process of arranging such treatment (including the various potential legal issues, such as consent) should thereby become simpler. However, there are no current plans to establish a formal scientific trial of intraventricular PPS and the treatment is one that is being given essentially on a speculative basis. The present provision of IVPPS remains an individual decision between patient, family and their immediately responsible clinician, after full understanding and discussion of the facts as detailed above.

FLUPIRTINE

A study published in 2004 (Otto et al.) reported some beneficial effects on cognitive function in patients with CJD but there is no evidence for increased survival with the treatment.

Reference

Otto M et al. Efficacy of flupirtine on cognitive function in patients with CJD: a double-blind study. Neurology 2004; 62: 714-718.

MRC PRION1

As indicated above, the MRC has funded a formal treatment trial of CJD. The trial commenced in 2004. It is, initially, aiming to study Quinacrine. However, it may study other possible treatments in the future. It will also be reviewing and assessing individuals without treatment to obtain comparative data of the natural course of illness.

http://www.cjd.ed.ac.uk/TREAT.htm

Unsuccessful intraventricular PPS treatment of vCJD Sun Apr 9, 2006 09:59 71.248.149.104

1: Acta Neurochir (Wien). 2006 Apr 7; [Epub ahead of print]

Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease.

Whittle IR, Knight RS, Will RG.

Department of Clinical Neurosciences and National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK.

Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced.

........

In conclusion, cerebroventricular infusion of PPS at 11 mg/kg/d appears safe and well tolerated for continuous long-term application. Our patient has survived for 37 months after initial symptoms and 30 months after diagnosis of probable vCJD, while the median duration of illness with vCJD is 13 months (range 6–39)7. Further lessons have also been learned from this first case. Firstly, surgery in a brain affected by vCJD may result in a higher rate of surgical complications than might be expected in a normal patient. We suggest that in order to allow the catheter track to organise, drug infusion should be delayed for at least 7–10 days after implantation of the pump system. Regular neuroradiological followup throughout the treatment period is strongly recommended. Secondly, if clinically significant benefits are to be expected, PPS administration should start as early as possible in the course of the disease and before irreversible loss of neurological function has occurred. Further clinical, neuroradiological and laboratory investigations in the setting of a prospective clinical study with standardised follow-up protocol and data collection are essential in order to assess the efficacy of PPS administration in vCJD and in other prion diseases. ..........snip...end...TSS

Professor Will, well noted to me that "Unfortunately the treatment did not work in this individual but it is important not to conclude that the treatment could not work in other people."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16598408&query_hl=1&itool=pubmed_docsum

TSS