Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease
Article
Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease
Michael D. Geschwind, MD, PhD, Amy L. Kuo, MS, RN, GNP, Katherine S. Wong,
BA, Aissa Haman, MD, Gillian Devereux, MPH, RN, Benjamin J. Raudabaugh, BA,
David Y. Johnson, MD, Charles C. Torres-Chae, MPA, Ron Finley, BSPharm, RPh,
CGP, Paul Garcia, MD, Julie N. Thai, MPH, Hugo Q. Cheng, MD, John M. Neuhaus,
PhD, Sven A. Forner, BS, Jacque L. Duncan, MD, Katherine L. Possin, PhD, Stephen
J. DeArmond, MD, PhD, Stanley B. Prusiner, MD and Bruce L. Miller, MD +Show
Affiliations
| + Show Full Disclosures
Correspondence to Dr. Geschwind: mgeschwind@memory.ucsf.edu
Published online before print October 11, 2013, doi:
10.1212/WNL.0b013e3182a9f3b4 Neurology 10.1212/WNL.0b013e3182a9f3b4
Abstract Full Text (PDF) Also available: Data Supplement
Abstract
Objective: To determine whether oral quinacrine increases survival in
sporadic Creutzfeldt-Jakob disease (sCJD).
Methods: This NIH/National Institute on Aging–funded, double-blinded,
placebo-controlled, stratified randomization treatment trial was conducted at
the University of California, San Francisco from February 2005 through May 2009
(ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to
quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and
planned for months 2, 6, and 12. Subjects returning for their month-2 visit were
offered open-label quinacrine. The primary outcome was survival from
randomization to month 2.
Results: Of 425 patients referred, 69 subjects enrolled, 54 subjects were
randomized to active drug or placebo, and 51 subjects with sCJD were included in
survival analyses. Survival for the randomized portion of the trial (first 2
months) showed no significant difference between the 2 groups (log-rank
statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine
compared with placebo, 95% confidence interval = 0.58, 3.53). The
quinacrine-treated group, however, declined less on 2 of 3 functional scales,
the modified Rankin and Clinical Dementia Rating, than the placebo group during
the first 2 months.
Conclusion: This interventional study provides Class I evidence that oral
quinacrine at 300 mg per day does not improve 2-month survival of patients with
sCJD, compared with placebo. Importantly, this study shows that double-blinded,
placebo-controlled, randomized treatment trials are possible in prion disease.
Furthermore, the quantitative data collected on the course of sCJD will be
useful for future trials.
Classification of evidence: This study provides Class I evidence that
quinacrine does not improve survival for people with sCJD when given orally at a
dose of 300 mg per day for 2 months.
Received November 6, 2012. Accepted in final form August 1, 2013. © 2013
American Academy of Neurology
>>>That’s a big challenge, but it’s also a big relief that the
scientific community has now uncovered this problem. In retrospect, strain
selection and drug resistance probably explain why quinacrine never worked in
animals or humans even though it worked brilliantly in a test tube. Armed with
this new information, you can bet that the UCSF folks and many other groups will
be working hard to find drugs that apply universally across all strains of
prions. Dr. Prusiner briefly flashed a slide touting some of the new compounds
they’ve discovered and are currently following up on. Hopefully this will mean
that by the time we finally do see a new drug in clinical trials, it will work a
whole lot better than quinacrine did. Having things not work is disappointing –
but learning why they didn’t work is a huge step forward. <<<
see ;
Highlights of Prion2013 Posted on June 2, 2013 by admin This past week we
had the privilege of going to Banff to attend Prion2013, the biggest annual
conference on prions. We were truly impressed and humbled by the wealth of
progress being made on understanding the basic science of prions and on
developing therapeutics. We also got to meet many top scientists including
several of our own collaborators who we’d never met face-to-face.
Here are a few of the major themes of the conference.
de novo prions in a test tube
It’s been three decades since Stanley Prusiner coined the term prion,
ushering in our modern understanding that misfolding can induce misfolding
[Prusiner 1982]. The ‘prion hypothesis’ – in short, the notion that proteins can
be infectious and cause disease – has long since ceased to be controversial. But
it has long been held that the “final final final” proof of the prion hypothesis
would be to generate synthetic prions from purified proteins in a test tube and
show that they’re infectious.
This has proven surprisingly difficult to do. Until recently, all of the de
novo prions anyone had managed to create all had one or another Shakespearan
flaw that made them “not count” – they used mutant prion protein [Legname 2004],
used existing infectious prions to seed the reaction [Castilla 2005] or used
cells rather than purified protein [Edgeworth 2010]. Finally a few years ago,
Fei Wang and Jiyan Ma managed to pull it off [Wang 2010], but people still
doubted them. Wang and Ma had used an extremely sensitive amplification
technique, so people wondered if maybe they hadn’t created anything new but had
just inadvertently amplified a single prion particle that had floated into the
test tube from their lab, where they’d done prion research for years.
To disprove the doubters, Prof. Ma set up a brand new lab at East China
Normal University in Shanghai, where no one had ever done prion research before
and no prions would be just lying around, and he repeated the experiment there
(with success). This seems to have finally done the trick: everyone was
convinced enough that they gave Ma’s protege, Fei Wang, the conference’s annual
prize for best research.
they’re all prions
The conference wasn’t just about Creutzfeldt-Jakob Disease, fatal familial
insomnia, BSE, and the other ‘classical’ prion diseases. There were also several
talks on Alzheimer’s, Parkinson’s, and ALS, with the unifying theme that each of
these diseases involves a misfolded protein that, on contact, can induce a
correctly folded copy of itself to misfold. In short: these are prion diseases
too. This seems increasingly well-accepted – hypotheses that seemed
controversial even a year ago have gained currency, with big-name scientists
like Virginia Lee, Neil Cashman, and Mathias Jucker leading the way. Stanley
Prusiner showed a slide listing a couple dozen disorders that he now considers
to be prion diseases.
This is all bad news for Googleability: if just about every
neurodegenerative disease is a prion disease, then how are we going to find
relevant search results for actual prion diseases? We’re not changing our name
to “Transmissible Spongiform Encephalopathy Alliance”, that’s for sure.
But in seriousness, this is all a huge leap forward in our understanding of
these other diseases, and perhaps ultimately in our understanding and treatment
of, er, PrP diseases, if you will. Chris Dobson gave a brilliant talk about the
structural similarities of amyloid between a wide range of different proteins
and diseases and noted his hope of finding a drug that can act against all of
them – “the equivalent of a statin for heart disease”. As of today this is
science fiction, but there is no doubt that there are similarities between these
diseases, and advances in one promise to shed light on all.
strain selection, evolution and drug resistance
Prions come in different strains. In humans, FFI, GSS, familial CJD, vCJD,
kuru, and several subtypes of CJD (MM1, MM2, VV1, etc.) are considered to be
distinct strains of prion, meaning distinct misfolded conformations of prion
protein. But that’s not all – it turns out that each one of these is not just a
single strain, but most probably a collection of different strains (some call
them ‘quasi-species’) each with its own properties. This is a huge challenge for
developing prion therapeutics. The Prusiner lab’s work on 2-aminothiazoles as
potential drugs, revealed at the conference, showed that drugs effective against
mouse prion strains used in the lab aren’t necessarily effective against
Creutzfeldt-Jakob Disease prions. Not only that, but even the mouse prion
strains eventually develop resistance as the drug selects for the few
conformations of the protein that can form even in the presence of the
drug.
That’s a big challenge, but it’s also a big relief that the scientific
community has now uncovered this problem. In retrospect, strain selection and
drug resistance probably explain why quinacrine never worked in animals or
humans even though it worked brilliantly in a test tube. Armed with this new
information, you can bet that the UCSF folks and many other groups will be
working hard to find drugs that apply universally across all strains of prions.
Dr. Prusiner briefly flashed a slide touting some of the new compounds they’ve
discovered and are currently following up on. Hopefully this will mean that by
the time we finally do see a new drug in clinical trials, it will work a whole
lot better than quinacrine did. Having things not work is disappointing – but
learning why they didn’t work is a huge step forward.
Thursday, October 15, 2009
ANA: No Benefit for Quinacrine in CJD
December 13, 2012
The rise and fall of pentosan polysulfate in prion disease
kind regards,
terry
posted by Terry S. Singeltary Sr. at
9:12 PM
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