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Article: A robust and flexible baculovirus-insect cell system for AAV vector production with improved yield, capsid ratios and potency.

Marwidi, Yoko / Nguyen, Hoang-Oanh B / Santos, David / Wangzor, Tenzin / Bhardwaj, Sumita / Ernie, Gabriel / Prawdzik, Gregg / Lew, Garrett / Shivak, David / Trias, Michael / Padilla, Jada / Tran, Hung / Meyer, Kathleen / Surosky, Richard / Ward, Alex Michael

Molecular therapy. Methods & clinical development

2024 Volume 32, Issue 2, Page(s) 101228

Abstract: Manufacturing of adeno-associated viruses (AAV) for gene and cell therapy applications has increased significantly and spurred development of improved mammalian and insect cell-based production systems. We developed a baculovirus-based insect cell ... ...

Abstract	Manufacturing of adeno-associated viruses (AAV) for gene and cell therapy applications has increased significantly and spurred development of improved mammalian and insect cell-based production systems. We developed a baculovirus-based insect cell production system-the SGMO Helper-with a novel gene architecture and greater flexibility to modulate the expression level and content of individual Rep and Cap proteins. In addition, we incorporated modifications to the AAV6 capsid sequence that improves yield, capsid integrity, and potency. Production of recombinant AAV 6 (rAAV6) using the SGMO Helper had improved yields compared to the Bac-RepCap helper from the Kotin lab. SGMO Helper-derived rAAV6 is resistant to a previously described proteolytic cleavage unique to baculovirus-insect cell production systems and has improved capsid ratios and potency,
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2024.101228
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Article ; Online: Use of a 2-aminothiazole to Treat Chronic Wasting Disease in Transgenic Mice.

Berry, David / Giles, Kurt / Oehler, Abby / Bhardwaj, Sumita / DeArmond, Stephen J / Prusiner, Stanley B

The Journal of infectious diseases

2015 Volume 212 Suppl 1, Page(s) S17–25

Abstract: Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice ... ...

Abstract	Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice infected with prions that caused scrapie in sheep or prions that caused chronic wasting disease (CWD; hereafter "CWD prions") in deer, using 2 isolates for each disease. IND24 doubled the incubation times for mice infected with CWD prions but had no effect on the survival of those infected with scrapie prions. Biochemical, neuropathologic, and cell culture analyses were used to characterize prion strain properties following treatment, and results indicated that the CWD prions were not altered by IND24, regardless of survival extension. These results suggest that IND24 may be a viable candidate for treating CWD in infected captive cervid populations and raise questions about why some prion strains develop drug resistance whereas others do not.
MeSH term(s)	Animals ; Brain/pathology ; Cell Line ; Deer ; Drug Resistance/drug effects ; Female ; Kaplan-Meier Estimate ; Mice ; Mice, Transgenic ; Prions/metabolism ; Rabbits ; Scrapie/drug therapy ; Scrapie/mortality ; Sheep ; Thiazoles/pharmacology ; Thiazoles/therapeutic use ; Wasting Disease, Chronic/drug therapy ; Wasting Disease, Chronic/mortality
Chemical Substances	Prions ; Thiazoles ; 2-aminothiazole (5K8WKN668K)
Language	English
Publishing date	2015-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiu656
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Article ; Online: Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

Watts, Joel C / Giles, Kurt / Saltzberg, Daniel J / Dugger, Brittany N / Patel, Smita / Oehler, Abby / Bhardwaj, Sumita / Sali, Andrej / Prusiner, Stanley B

Journal of virology

2016 Volume 90, Issue 21, Page(s) 9558–9569

Abstract: The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE ...

Abstract	The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP Importance: Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.
MeSH term(s)	Animals ; Brain/metabolism ; Cattle ; Creutzfeldt-Jakob Syndrome/metabolism ; Creutzfeldt-Jakob Syndrome/pathology ; Creutzfeldt-Jakob Syndrome/transmission ; Encephalopathy, Bovine Spongiform/metabolism ; Encephalopathy, Bovine Spongiform/pathology ; Encephalopathy, Bovine Spongiform/transmission ; Guinea Pigs ; Humans ; Mice ; Mice, Transgenic ; Prion Proteins/metabolism ; Prions/metabolism
Chemical Substances	Prion Proteins ; Prions
Language	English
Publishing date	2016-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01106-16
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Article ; Online: Towards authentic transgenic mouse models of heritable PrP prion diseases.

Watts, Joel C / Giles, Kurt / Bourkas, Matthew E C / Patel, Smita / Oehler, Abby / Gavidia, Marta / Bhardwaj, Sumita / Lee, Joanne / Prusiner, Stanley B

Acta neuropathologica

2016 Volume 132, Issue 4, Page(s) 593–610

Abstract: Attempts to model inherited human prion disorders such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We ... ...

Abstract	Attempts to model inherited human prion disorders such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease-specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8-kDa proteinase K-resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity.
MeSH term(s)	Animals ; Brain/pathology ; Creutzfeldt-Jakob Syndrome/metabolism ; Creutzfeldt-Jakob Syndrome/pathology ; Disease Models, Animal ; Gerstmann-Straussler-Scheinker Disease/metabolism ; Gerstmann-Straussler-Scheinker Disease/pathology ; Mice, Transgenic ; Mutant Proteins/metabolism ; PrPSc Proteins/metabolism ; Prion Diseases/metabolism
Chemical Substances	Mutant Proteins ; PrPSc Proteins
Language	English
Publishing date	2016-06-28
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-016-1585-6
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Article ; Online: Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice.

Giles, Kurt / Berry, David B / Condello, Carlo / Dugger, Brittany N / Li, Zhe / Oehler, Abby / Bhardwaj, Sumita / Elepano, Manuel / Guan, Shenheng / Silber, B Michael / Olson, Steven H / Prusiner, Stanley B

The Journal of pharmacology and experimental therapeutics

2016 Volume 358, Issue 3, Page(s) 537–547

Abstract: Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical ... ...

Abstract	Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure-activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.
MeSH term(s)	Amides/chemistry ; Amides/metabolism ; Amides/pharmacology ; Amides/therapeutic use ; Animals ; Brain/drug effects ; Brain/metabolism ; Creutzfeldt-Jakob Syndrome/drug therapy ; Drug Discovery ; Female ; Mice ; Prion Diseases/drug therapy ; Prion Diseases/metabolism ; Structure-Activity Relationship ; Survival Analysis
Chemical Substances	Amides
Language	English
Publishing date	2016-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.116.235556
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Article: Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein

Watts, Joel C / Giles, Kurt / Stöhr, Jan / Oehler, Abby / Bhardwaj, Sumita / Grillo, Sunny K / Patel, Smita / DeArmond, Stephen J / Prusiner, Stanley B

Proceedings of the National Academy of Sciences of the United States of America. 2012 Feb. 28, v. 109, no. 9

2012

Abstract: Currently, there are no animal models of the most common human prion disorder, sporadic Creutzfeldt-Jakob disease (CJD), in which prions are formed spontaneously from wild-type (WT) prion protein (PrP). Interestingly, bank voles (BV) exhibit an ... ...

Abstract	Currently, there are no animal models of the most common human prion disorder, sporadic Creutzfeldt-Jakob disease (CJD), in which prions are formed spontaneously from wild-type (WT) prion protein (PrP). Interestingly, bank voles (BV) exhibit an unprecedented promiscuity for diverse prion isolates, arguing that bank vole PrP (BVPrP) may be inherently prone to adopting misfolded conformations. Therefore, we constructed transgenic (Tg) mice expressing WT BVPrP. Tg(BVPrP) mice developed spontaneous CNS dysfunction between 108 and 340 d of age and recapitulated the hallmarks of prion disease, including spongiform degeneration, pronounced astrogliosis, and deposition of alternatively folded PrP in the brain. Brain homogenates of ill Tg(BVPrP) mice transmitted disease to Tg(BVPrP) mice in ∼35 d, to Tg mice overexpressing mouse PrP in under 100 d, and to WT mice in ∼185 d. Our studies demonstrate experimentally that WT PrP can spontaneously form infectious prions in vivo. Thus, Tg(BVPrP) mice may be useful for studying the spontaneous formation of prions, and thus may provide insight into the etiology of sporadic CJD.
Keywords	Clethrionomys glareolus ; Creutzfeldt-Jakob Syndrome ; animal models ; brain ; humans ; mice ; prions ; voles
Language	English
Dates of publication	2012-0228
Size	p. 3498-3503.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Modulation of Creutzfeldt-Jakob disease prion propagation by the A224V mutation.

Watts, Joel C / Giles, Kurt / Serban, Ana / Patel, Smita / Oehler, Abby / Bhardwaj, Sumita / Guan, Shenheng / Greicius, Michael D / Miller, Bruce L / DeArmond, Stephen J / Geschwind, Michael D / Prusiner, Stanley B

Annals of neurology

2015 Volume 78, Issue 4, Page(s) 540–553

Abstract: Objective: Mutations in the gene encoding the prion protein (PrP) are responsible for approximately 10 to 15% of cases of prion disease in humans, including Creutzfeldt-Jakob disease (CJD). Here, we report on the discovery of a previously unreported C- ... ...

Abstract	Objective: Mutations in the gene encoding the prion protein (PrP) are responsible for approximately 10 to 15% of cases of prion disease in humans, including Creutzfeldt-Jakob disease (CJD). Here, we report on the discovery of a previously unreported C-terminal PrP mutation (A224V) in a CJD patient exhibiting a disease similar to the rare VV1 subtype of sporadic (s) CJD and investigate the role of this mutation in prion replication and transmission. Methods: We generated transgenic (Tg) mice expressing human PrP with the V129 polymorphism and A224V mutation, denoted Tg(HuPrP,V129,A224V) mice, and inoculated them with different subtypes of sCJD prions. Results: Transmission of sCJD VV2 or MV2 prions was accelerated in Tg(HuPrP,V129,A224V) mice, compared to Tg(HuPrP,V129) mice, with incubation periods of ∼110 and ∼210 days, respectively. In contrast, sCJD MM1 prions resulted in longer incubation periods in Tg(HuPrP,V129,A224V) mice, compared to Tg(HuPrP,V129) mice (∼320 vs. ∼210 days). Prion strain fidelity was maintained in Tg(HuPrP,V129,A224V) mice inoculated with sCJD VV2 or MM1 prions, despite the altered replication kinetics. Interpretation: Our results suggest that A224V is a risk factor for prion disease and modulates the transmission behavior of CJD prions in a strain-specific manner, arguing that residues near the C-terminus of PrP are important for controlling the kinetics of prion replication.
MeSH term(s)	Animals ; Brain/pathology ; Creutzfeldt-Jakob Syndrome/diagnosis ; Creutzfeldt-Jakob Syndrome/genetics ; Cricetinae ; Female ; Humans ; Mesocricetus ; Mice ; Mice, Transgenic ; Middle Aged ; Mutation/genetics ; Peptide Fragments/genetics ; PrPSc Proteins/genetics ; Prions/genetics
Chemical Substances	Peptide Fragments ; PrPSc Proteins ; Prions ; prion protein (125-228), human
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.24463
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Article ; Online: Protease-resistant prions selectively decrease Shadoo protein.

Watts, Joel C / Stöhr, Jan / Bhardwaj, Sumita / Wille, Holger / Oehler, Abby / Dearmond, Stephen J / Giles, Kurt / Prusiner, Stanley B

PLoS pathogens

2011 Volume 7, Issue 11, Page(s) e1002382

Abstract: The central event in prion diseases is the conformational conversion of the cellular prion protein (PrP(C)) into PrP(Sc), a partially protease-resistant and infectious conformer. However, the mechanism by which PrP(Sc) causes neuronal dysfunction remains ...

Abstract	The central event in prion diseases is the conformational conversion of the cellular prion protein (PrP(C)) into PrP(Sc), a partially protease-resistant and infectious conformer. However, the mechanism by which PrP(Sc) causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho), a protein that resembles the flexibly disordered N-terminal domain of PrP(C), were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrP(Sc) in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrP(Sc). Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrP(Sc). Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrP(Sc) during prion disease.
MeSH term(s)	Animals ; Brain/enzymology ; Brain/metabolism ; Cell Line ; Down-Regulation ; GPI-Linked Proteins ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/metabolism ; Neurons/enzymology ; Neurons/metabolism ; Peptide Hydrolases/metabolism ; PrPC Proteins/chemistry ; PrPC Proteins/metabolism ; PrPSc Proteins/chemistry ; PrPSc Proteins/metabolism ; Prion Diseases/metabolism ; Prion Diseases/veterinary ; Sheep ; Sheep Diseases/metabolism
Chemical Substances	GPI-Linked Proteins ; Nerve Tissue Proteins ; PrPC Proteins ; PrPSc Proteins ; Sprn protein, mouse ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2011-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1002382
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Article ; Online: Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains.

Giles, Kurt / Berry, David B / Condello, Carlo / Hawley, Ronald C / Gallardo-Godoy, Alejandra / Bryant, Clifford / Oehler, Abby / Elepano, Manuel / Bhardwaj, Sumita / Patel, Smita / Silber, B Michael / Guan, Shenheng / DeArmond, Stephen J / Renslo, Adam R / Prusiner, Stanley B

The Journal of pharmacology and experimental therapeutics

2015 Volume 355, Issue 1, Page(s) 2–12

Abstract: Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold ... ...

Abstract	Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from ∼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, β-sheet-rich "scrapie" isoform (PrP(Sc)) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrP(Sc) and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrP(Sc) accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrP(Sc) that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions.
MeSH term(s)	Animals ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Dose-Response Relationship, Drug ; Female ; Humans ; Mice ; PrPSc Proteins/genetics ; PrPSc Proteins/metabolism ; Scrapie/pathology ; Species Specificity ; Survival Analysis ; Survival Rate ; Thiazoles/chemistry ; Thiazoles/pharmacokinetics ; Thiazoles/pharmacology ; Thiazoles/therapeutic use ; Transgenes/genetics ; Treatment Outcome
Chemical Substances	PrPSc Proteins ; Thiazoles ; 2-aminothiazole (5K8WKN668K)
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.115.224659
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Article ; Online: Drug resistance confounding prion therapeutics.

Berry, David B / Lu, Duo / Geva, Michal / Watts, Joel C / Bhardwaj, Sumita / Oehler, Abby / Renslo, Adam R / DeArmond, Stephen J / Prusiner, Stanley B / Giles, Kurt

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 44, Page(s) E4160–9

Abstract: There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best ... ...

Abstract	There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt-Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.
MeSH term(s)	Animals ; Brain/pathology ; Cell Line ; DNA Primers/genetics ; Drug Discovery ; Drug Resistance/genetics ; Female ; Humans ; Immunoblotting ; Luminescent Measurements ; Mice ; Neurodegenerative Diseases/drug therapy ; Prions/antagonists & inhibitors ; Prions/genetics ; Thiazoles/pharmacology
Chemical Substances	DNA Primers ; Prions ; Thiazoles ; 2-aminothiazole (5K8WKN668K)
Language	English
Publishing date	2013-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1317164110
Database	MEDical Literature Analysis and Retrieval System OnLINE

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