Saturday, October 5, 2013

Prospective Grant of Exclusive License: Use of Quaking-Induced Conversion (QUIC) for Detection of Prions

Sent: Saturday, October 05, 2013 11:33 AM
Subject: Prospective Grant of Exclusive License: Use of Quaking-Induced Conversion (QUIC) for Detection of Prions

[Federal Register Volume 78, Number 192 (Thursday, October 3, 2013)]
[Page 61375]
From the Federal Register Online via the Government Printing Office []
[FR Doc No: 2013-24141]
National Institutes of Health
Prospective Grant of Exclusive License: Use of Quaking-Induced Conversion (QUIC) for Detection of Prions
AGENCY: National Institutes of Health, HHS.
ACTION: Notice.
SUMMARY: This is notice, in accordance with 35 U.S.C. 209 and 37 CFR part 404, that the National Institutes of Health (NIH), Department of Health and Human Services, is contemplating the grant of an exclusive license to practice the inventions embodied in U.S. provisional Application 60/961,364 filed July 20, 2007 [E-109-2007/0-US-01], PCT/ US2008/070656, filed July 21, 2008; [E-109-2007/1-PCT-01], EPC application No 08796382.3 filed July 21, 2008 [E-109-2007/1-EP-03], US Application No. 12/177,012, filed July 21, 2008 and issued as US patent 8,216,788 on July 10, 2012 [E-109-2007/1-US-02], and US Application No. 13/489,321, filed June 5, 2012 [E-109-2007/1-US-04]; Each entitled ``Detection of Infectious Prion Protein by Seeded Conversion of Recombinant Prion Protein'' By Byron Caughey et al. to Prionics AG having a place of business at Wagistrasse 27a CH-8952 Schlieren-Zurich, Switzerland. The patent rights in this invention have been assigned to the United States of America.
DATES: Only written comments and/or application for a license that are received by the NIH Office of Technology Transfer on or before November 4, 2013 will be considered.
ADDRESSES: Requests for a copy of the patent application, inquiries, comments and other materials relating to the contemplated license should be directed to: Tedd Fenn, Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, MD 20852-3804; Email:; Telephone: 301-435-5031; Facsimile: 301-402-0220.
The prospective worldwide exclusive license will be royalty bearing and will comply with the terms and conditions of 35 U.S.C. 209 and 37 CFR part 404. The prospective exclusive license may be granted unless, within thirty (30) days from the date of this published Notice, NIH receives written evidence and argument that establishes that the grant of the license would not be consistent with the requirements of 35 U.S.C. 209 and 37 CFR part 404.
The invention relates to methods and compositions for the detection of infectious proteins or prions and diagnosis of prion related diseases. Prion diseases are neurodegenerative diseases of great public concern because humans may be infected from hoofed animals used as food, food products such as milk, or blood products. Currently available tests for disease-causing prions are either incapable of detecting low concentrations of prions and must be used post-mortem or are incapable of detecting low concentrations of prions economically or accurately. This technology enables rapid and economical detection of sub-lethal concentrations of prions by using recombinant, normal, prion protein (rPrP-sen) as a marker or indicator of infectious prions in a sample. Specifically, prions (contained in a sample) seed the polymerization of rPrP-sen, and polymerized rPrP-sen is detected as an amplified indicator of prions in the sample. This assay differs from the protein-misfolding cyclic amplification assay (PMCA) because it enables the effective use of rPrP-sen and does not require multiple amplification cycles unless a higher degree of sensitivity is required. It is anticipated that this technology can be combined with additional prion-detection technologies to further improve the sensitivity of the assay. In its current embodiment, this assay has been used to detect prions in brain tissue or cerebral spinal fluid (CSF) from humans (variant CJD), sheep (scrapie), and hamsters (scrapie). The proposed field of exclusivity may be limited to diagnostics requiring premarket approval by a U.S. or a foreign regulatory agency.
Properly filed competing applications for a license filed in response to this notice will be treated as objections to the contemplated license. Comments and objections submitted in response to this notice will not be made available for public inspection, and, to the extent permitted by law, will not be released under the Freedom of Information Act, 5 U.S.C. 552.
Dated: September 27, 2013.
Richard U. Rodriguez, Director, Division of Technology Development & Transfer, Office of Technology Transfer, National Institutes of Health. [FR Doc. 2013-24141 Filed 10-2-13; 8:45 am] BILLING CODE 4140-01-P
JAMES ROBERTSON United States District Judge
The government's additional argument, that private testing 14 somehow would interfere with USDA's surveillance program, is unexplained and therefore rejected. Of greater concern is the possibility that private testing 15 could produce a false positive result, which might trigger unnecessary public alarm. USDA has asserted this possibility as a reason to avoid private testing. Indeed, the Bio-Rad kits that Creekstone proposes using are used throughout the world, including as part of the USDA's own surveillance testing. - 18 -
Invited.16: Studies of chronic wasting disease transmission in cervid and non-cervid species
Edward A, Hoover,1 Candace K. Mathiason,1 Davin M. Henderson,1 Nicholas J. Haley,1 Davis M. Seelig,1 Nathaniel D. Denkers,1 Amy V. Nalls,1 Mark D. Zabe,1 Glenn C. Telling,1 Fernando Goni2 and Thomas Wisniewski,2
1Prion Research Center; Colorado State University; Fort Collins, CO USA; 2New York University School of Medicine; New York, NY USA
How and why some misfolded proteins become horizontally transmitted agents and occasionally cross species barriers are issues fundamental to understanding prion disease. Chronic wasting disease (CWD) of cervids is perhaps a prototype of horizontal prion transmission, encompassing efficient mucosal uptake, lymphoid amplification, neuroinvasion, peripheralization, and dissemination via mucosal excretion. Efficient mucosal transmission of CWD in deer has been demonstrated by oral, nasal, aerosol, and indirect contact exposure. In addition, other studies (Mathiason CK, et al.) reported at the symposium support a significant role for pre- and/or postnatal transmission of CWD from doe to offspring. Accumulating, yet still incomplete, evidence also suggests that the period of relatively covert CWD infection may be longer than originally thought. Given the above, minimally invasive sensitive assays based on body fluids from live animals would aid substantially in understanding the biology of CWD. We have been applying seeded realtirne quaking-induced amplification of recombinant PrP substrates (i.e., RT-QuIC methodology) to: (1) investigate antemortem CWD detection, and (2) model PrP-based species barriers and trans-species adaptation-topics we previously explored using sPMCA and in vivo bioassays. At this symposium, we report sensitive and specific detection CWD prions in saliva, urine, blood (Mathiason lab), and rectal and pharyngeal lymph node samples (Haley NJ, et al.) from pre-symptomatic and symptomatic experimentally and naturally exposed deer. Other ongoing studies are employing RT-QuIC methodology to model amplification barriers among CWD, FSE, BSE, and CJD prions using cervine, feline, bovine, human, and promiscuous rPrP substrates and the above species prion seeds, cellular co-factors, and transgenic mice. Finally, in collaboration with the Wisniewski laboratory, we are conducting of experimental CWD vaccination studies in deer employing oral administration of an attenuated Salmonella vector expressing cervid PrP epitopes.
AD.06: Detecting prions in the brain and blood of TSE-infected deer and hamsters
Alan Elder,1 Davin Henderson,1 Anca Selariu,1 Amy Nalls,1 Byron Caughey,2 Richard Bessen,1 Jason Bartz3 and Candace Mathiason1
1Colorado State University; Fort Collins, CO USA; 2NIH Rocky Mountain Laboratories; Hamilton, MT USA; 3Creighton University; Omaha, NE USA
While large quantities of protease resistant prion protein (PrPres) can be demonstrated by western blot or IHC in lymphoid biopsies or post-mortem brain tissues harvested from prion-infected animals, these conventional assays are less reliable as means to detect the small quantities of prions thought to be present in bodily fluids or associated with early and asymptomatic phases of TSE disease. The Real Time-Quaking Induced Conversion (RT-QuIC) assay is capable of detecting prions at concentrations below the level of sensitivity of conventional assays and provides a real-time fluorescent readout negating the use of proteases. We have made modifications to the RT-QuIC assay to utilize it for the detection of PrPres in brain and blood harvested from various species infected with prions. In this study, we analyzed CWD-infected deer and CWD/TME-infected hamster whole blood to determine the effect of:
(1) various anticoagulants,
(2) freezing and
(3) NaPTA precipitation.
Brain tissue and blood collected from naive deer and hamsters served as negative controls.
We were able to demonstrate amplifiable prions in
(1) brain and blood samples harvested from CWD/TME-infected animals,
(2) heparinized blood,
(3) frozen vs. fresh blood and
(4) NaPTA treated samples.
The RT-QuIC assay is able to detect PrPres in various species of animals and shows promise as an antemortem diagnostic tool for blood-borne TSEs.
Oral.08: Mother to offspring transmission of chronic wasting disease in Reeve's Muntjac deer
Amy Nalls,1 Erin McNulty,1 Jenny Powers,2 Davis Seelig,1 Clare Hoover,1 Nicholas Haley,1 Jeanette Hayes-Klug,1 Kelly Anderson,1 Paula Stewart,3 Wilfred Goldmann,3 Edward A. Hoover1 and Candace K. Mathiason1
1Colorado State University; Fort Collins, CO USA; 2National Park Service; Fort Collins, CO USA; 3The Roslin Institute and Royal School of Veterinary Studies; Edinburgh, UK
To investigate the role mother to offspring transmission plays in chronic wasting disease (CWD), we have developed a cervid model employing the Reeve's muntjac deer (Muntiacus reevesi). Eight muntjac doe were orally inoculated with CWD and tested PrPCWD lymphoid positive by 4 mo post infection. Fourteen fawns were born to these eight CWD-infected doe-3 were born viable, 6 were born non-viable and 5 were harvested as fetuses from early or end-stage CWD-infected doe. All three viable fawns have demonstrated CWD IHC lymphoid biopsy positivity between 43 d post birth and 11 mo post birth. Two of these three CWD positive viable offspring have developed clinical signs consistent with TSE disease (28-33 mo post birth). Moreover, CWD prions have been detected by sPMCA in 11 of 16 tissues harvested from 6 full-term non-viable fawns and in 7 of 11 fetal tissues harvested in utero from the second and third trimester fetuses. Additional tissues and pregnancy related fluids from doe and offspring are being analyzed for CWD prions. In summary, using the muntjac deer model we have demonstrated CWD clinical disease in offspring born to CWD-infected doe, and in utero transmission of CWD from mother to offspring. These studies provide basis to further investigate the mechanisms of maternal transfer of prions.
AD.63: Susceptibility of domestic cats to chronic wasting disease
Amy V.Nalls,1 Candace Mathiason,1 Davis Seelig,2 Susan Kraft,1 Kevin Carnes,1 Kelly Anderson,1 Jeanette Hayes-Klug1 and Edward A. Hoover1
1Colorado State University; Fort Collins, CO USA; 2University of Minnesota; Saint Paul, MN USA
Domestic and nondomestic cats have been shown to be susceptible to feline spongiform encephalopathy (FSE), almost certainly caused by consumption of bovine spongiform encephalopathy (BSE)-contaminated meat. Because domestic and free-ranging nondomestic felids scavenge cervid carcasses, including those in areas affected by chronic wasting disease (CWD), we evaluated the susceptibility of the domestic cat (Felis catus) to CWD infection experimentally. Cohorts of 5 cats each were inoculated either intracerebrally (IC) or orally (PO) with CWD-infected deer brain. At 40 and 42 mo post-inoculation, two IC-inoculated cats developed signs consistent with prion disease, including a stilted gait, weight loss, anorexia, polydipsia, patterned motor behaviors, head and tail tremors, and ataxia, and progressed to terminal disease within 5 mo. Brains from these two cats were pooled and inoculated into cohorts of cats by IC, PO, and intraperitoneal and subcutaneous (IP/SC) routes. Upon subpassage, feline-adapted CWD (FelCWD) was transmitted to all IC-inoculated cats with a decreased incubation period of 23 to 27 mo. FelCWD was detected in the brains of all the symptomatic cats by western blotting and immunohistochemistry and abnormalities were seen in magnetic resonance imaging, including multifocal T2 fluid attenuated inversion recovery (FLAIR) signal hyper-intensities, ventricular size increases, prominent sulci, and white matter tract cavitation. Currently, 3 of 4 IP/SQ and 2 of 4 PO inoculared cats have developed abnormal behavior patterns consistent with the early stage of feline CWD. These results demonstrate that CWD can be transmitted and adapted to the domestic cat, thus raising the issue of potential cervid-to- feline transmission in nature.
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Prion2013 Chronic Wasting Disease CWD risk factors, humans, domestic cats, blood, and mother to offspring transmission
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RT-QuIC analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease
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***The Presence of Disease-Associated Prion Protein in Skeletal Muscle of Cattle Infected with Classical Bovine Spongiform Encephalopathy
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Atypical BSE: role of the E211K prion polymorphism
Location: Virus and Prion Research Unit
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Evaluation of the Zoonotic Potential of Transmissible Mink Encephalopathy
We previously described the biochemical similarities between PrPres derived from L-BSE infected macaque and cortical MM2 sporadic CJD: those observations suggest a link between these two uncommon prion phenotypes in a primate model (it is to note that such a link has not been observed in other models less relevant from the human situation as hamsters or transgenic mice overexpressing ovine PrP [28]). We speculate that a group of related animal prion strains (L-BSE, c-BSE and TME) would have a zoonotic potential and lead to prion diseases in humans with a type 2 PrPres molecular signature (and more specifically type 2B for vCJD)
Together with previous experiments performed in ovinized and bovinized transgenic mice and hamsters [8,9] indicating similarities between TME and L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME outbreaks in North America and Europe during the mid-1900s.
Sunday, August 11, 2013
Creutzfeldt-Jakob Disease CJD cases rising North America updated report August 2013
Creutzfeldt-Jakob Disease CJD cases rising North America with Canada seeing an extreme increase of 48% between 2008 and 2010
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Creutzfeldt-Jakob disease (CJD) biannual update August 2013 U.K. and Contaminated blood products induce a highly atypical prion disease devoid of PrPres in primates
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Minimise transmission risk of CJD and vCJD in healthcare settings Guidance