IP Library Granted Patent US 12,638,457
Granted Patent B2
US 12,638,457 · App. 17/767,549 · Granted May 26, 2026

RAN proteins as biomarkers in CAG/CTG expansion disorders

Inventors: Laura Ranum (Gainesville, FL); Monica Banez Coronel (Gainesville, FL)
Assignee: University of Florida Research Foundation, Incorporated
G01N33/6875G01N2800/28
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Quick Facts
Patent No.
US 12,638,457
App. No.
17/767,549
Granted
May 26, 2026
Kind
B2
Abstract

Aspects of the disclosure relate to methods and compositions (e.g., kits) for detecting certain repeat-associated non-ATG (RAN) proteins in a subject (e.g., a subject having or suspected of having a disease associated with a CAG and/or CTG repeat expansion). In some embodiments, methods described by the disclosure comprise detecting one or more RAN proteins in a biological sample obtained from a subject by an immunoassay using one or more antibodies that target homopolymeric repeat regions of RAN proteins. In some embodiments, the disclosure relates to kits comprising one or more antibodies that target homopolymeric repeat regions of RAN proteins, and an immunoassay plate and/or reagents. In some embodiments, the disclosure provides methods of producing anti-RAN protein antibodies.

Claims (12)

1 . A method of producing an antibody, the method comprising administering to a cell or a subject a peptide antigen consisting of the sequence set forth in any one of SEQ ID NOs: 17, 19-22, or 24-26.

2 . The method of claim 1 , further comprising the step of isolating the antibody from the subject.

3 . The method of claim 1 , wherein the cell is a mammalian cell.

4 . The method of claim 3 , wherein the mammalian cell is a B cell.

5 . The method of claim 1 , wherein the subject is mammal.

6 . The method of claim 3 , wherein the mammalian cell is a hybridoma cell.

7 . A method of producing an antibody, the method comprising administering to a cell or a subject a peptide antigen comprising the sequence set forth in SEQ ID NO: 18 or 23.

8 . The method of claim 7 , further comprising the step of isolating the antibody from the subject.

9 . The method of claim 7 , wherein the cell is a mammalian cell.

10 . The method of claim 9 , wherein the mammalian cell is a B cell.

11 . The method of claim 7 , wherein the subject is mammal.

12 . The method of claim 9 , wherein the mammalian cell is a hybridoma cell.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 6, 2022
From: RANUM, LAURA; CORONEL, MONICA BANEZ
To: UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED
Reel/Frame 060407/0404 →
Continuity (2)
Provisional Application 62913662 · Oct 10, 2019
Related Publication 20240069039A1 · Feb 29, 2024
References Cited (276)
US 5011912A · Hopp et al. · 1991 [cited by applicant]
US 6204008B1 · Borneman et al. · 2001 [cited by applicant]
US 6326151B1 · Katze et al. · 2001 [cited by applicant]
US 6342581B1 · Rosen et al. · 2002 [cited by applicant]
US 7008796B2 · Wohlstadter et al. · 2006 [cited by applicant]
US 7481997B1 · Hardy · 2009 [cited by applicant]
US 8993633B2 · Megeney et al. · 2015 [cited by applicant]
US 9448232B2 · Petrucelli et al. · 2016 [cited by applicant]
US 10066007B2 · Edbauer et al. · 2018 [cited by applicant]
US 10295547B2 · Ranum et al. · 2019 [cited by applicant]
US 10392447B2 · Montrasio et al. · 2019 [cited by applicant]
US 10509045B2 · Ranum et al. · 2019 [cited by applicant]
US 10663475B2 · Ranum et al. · 2020 [cited by applicant]
US 10940161B2 · Ranum et al. · 2021 [cited by applicant]
US 10961322B2 · Montrasio et al. · 2021 [cited by applicant]
US 11034974B2 · Ling et al. · 2021 [cited by applicant]
US 11345911B2 · Ranum et al. · 2022 [cited by applicant]
US 11903910B2 · Ranum et al. · 2024 [cited by applicant]
US 12025622B2 · Ranum et al. · 2024 [cited by applicant]
US 12162952B2 · Grimm et al. · 2024 [cited by applicant]
US 12360124B2 · Ranum et al. · 2025 [cited by applicant]
US 12364707B2 · Ranum et al. · 2025 [cited by applicant]
US 12392786B2 · Ranum et al. · 2025 [cited by applicant]
US 12436154B2 · Ranum et al. · 2025 [cited by applicant]
US 12473545B2 · Ranum et al. · 2025 [cited by applicant]
US 20020165355A1 · Meheus et al. · 2002 [cited by applicant]
US 20030113826A1 · Wehner et al. · 2003 [cited by applicant]
US 20030233675A1 · Cao et al. · 2003 [cited by applicant]
US 20050042657A1 · Weese-Mayer et al. · 2005 [cited by applicant]
US 20060068434A1 · Stoerker · 2006 [cited by applicant]
US 20070004729A1 · Timmer et al. · 2007 [cited by applicant]
US 20070014810A1 · Baker et al. · 2007 [cited by applicant]
US 20070036760A1 · Wilson et al. · 2007 [cited by applicant]
US 20070093426A1 · Wormser · 2007 [cited by applicant]
US 20080188457A1 · Barlow et al. · 2008 [cited by applicant]
US 20080227699A1 · Chiba et al. · 2008 [cited by applicant]
US 20080248099A1 · Ishii · 2008 [cited by applicant]
US 20090074721A1 · Kim et al. · 2009 [cited by applicant]
US 20090143418A1 · Dixon et al. · 2009 [cited by applicant]
US 20090148866A1 · Datwyler et al. · 2009 [cited by applicant]
US 20090312395A1 · El-Tanani et al. · 2009 [cited by applicant]
US 20100298280A1 · Kioschis-Schneider et al. · 2010 [cited by applicant]
US 20120076785A1 · Nikolaev et al. · 2012 [cited by applicant]
US 20120094299A1 · Ranum · 2012 [cited by examiner]
US 20120142027A1 · Kim · 2012 [cited by applicant]
US 20120220534A1 · Levin et al. · 2012 [cited by applicant]
US 20130085169A1 · Baghdoyan et al. · 2013 [cited by applicant]
US 20130115603A9 · Ranum et al. · 2013 [cited by applicant]
US 20140100282A1 · Wong · 2014 [cited by applicant]
US 20140336133A1 · Miller et al. · 2014 [cited by applicant]
US 20150011729A1 · Ranum et al. · 2015 [cited by applicant]
US 20150361166A1 · Edbauer et al. · 2015 [cited by applicant]
US 20160025747A1 · Ranum et al. · 2016 [cited by applicant]
US 20160096800A1 · Walter et al. · 2016 [cited by applicant]
US 20160346297A1 · Sheehan · 2016 [cited by applicant]
US 20170247471A1 · Montrasio et al. · 2017 [cited by applicant]
US 20180050001A1 · During et al. · 2018 [cited by applicant]
US 20180088111A1 · Ni et al. · 2018 [cited by applicant]
US 20180292416A1 · Ranum et al. · 2018 [cited by applicant]
US 20190142858A1 · Ranum et al. · 2019 [cited by applicant]
US 20190153445A1 · Seow et al. · 2019 [cited by applicant]
US 20190285652A1 · Ranum et al. · 2019 [cited by applicant]
US 20200010567A1 · Montrasio et al. · 2020 [cited by applicant]
US 20200140846A1 · Ranum et al. · 2020 [cited by applicant]
US 20200206255A9 · Ranum et al. · 2020 [cited by applicant]
US 20200232925A1 · Ranum et al. · 2020 [cited by applicant]
US 20200241013A1 · Ranum et al. · 2020 [cited by applicant]
US 20200268691A1 · Ranum et al. · 2020 [cited by applicant]
US 20200341012A1 · Ranum et al. · 2020 [cited by applicant]
US 20200355701A1 · Van Meter · 2020 [cited by applicant]
US 20210236535A1 · Ranum et al. · 2021 [cited by applicant]
US 20210285970A1 · Ranum et al. · 2021 [cited by applicant]
US 20210347866A1 · Wang et al. · 2021 [cited by applicant]
US 20220153874A1 · Grimm et al. · 2022 [cited by applicant]
US 20220202935A1 · Edbauer et al. · 2022 [cited by applicant]
US 20220373559A1 · Ranum et al. · 2022 [cited by applicant]
US 20230002753A1 · Ranum et al. · 2023 [cited by applicant]
US 20230218730A1 · Ranum et al. · 2023 [cited by applicant]
US 20230288434A1 · Ranum et al. · 2023 [cited by applicant]
US 20240269093A1 · Ranum et al. · 2024 [cited by applicant]
US 20240393348A1 · Ranum et al. · 2024 [cited by applicant]
US 20240426844A1 · Ranum et al. · 2024 [cited by applicant]
US 20250027084A1 · Wolin et al. · 2025 [cited by applicant]
US 20250041247A1 · Ranum et al. · 2025 [cited by applicant]
US 20250164489A1 · Ranum et al. · 2025 [cited by applicant]
US 20250177431A1 · Richter et al. · 2025 [cited by applicant]
US 20250237666A9 · Ranum et al. · 2025 [cited by applicant]
CA 3137666A1 · 2020 [cited by applicant]
EP 2837390A1 · 2015 [cited by applicant]
EP 2948471A1 · 2015 [cited by applicant]
EP 3440100A1 · 2019 [cited by applicant]
JP H11344491A · 1999 [cited by applicant]
JP 2004510162 · 2004 [cited by applicant]
JP 2004518437A · 2004 [cited by applicant]
JP 2004520803A · 2004 [cited by applicant]
JP 2007507223A · 2007 [cited by applicant]
JP 2012501193A · 2012 [cited by applicant]
JP 2016515208A · 2016 [cited by applicant]
JP 2016180665A · 2016 [cited by applicant]
JP 2017019773A · 2017 [cited by applicant]
JP 2017205118A · 2017 [cited by applicant]
JP 2018031780 · 2018 [cited by applicant]
JP 2019515894A · 2019 [cited by applicant]
WO WO200175067A2 · 2001 [cited by applicant]
WO WO2001081581A2 · 2001 [cited by applicant]
WO WO2002027317A2 · 2002 [cited by applicant]
WO WO2002040672A2 · 2002 [cited by applicant]
WO WO2002062945A2 · 2002 [cited by applicant]
WO WO2005033321A2 · 2005 [cited by applicant]
WO WO2006083800A2 · 2006 [cited by applicant]
WO WO2009144480A1 · 2009 [cited by applicant]
WO WO2010115033A2 · 2010 [cited by applicant]
WO WO2010132982A1 · 2010 [cited by applicant]
WO WO2011052906A2 · 2011 [cited by applicant]
WO WO2012159754A2 · 2012 [cited by applicant]
WO WO2013030588A1 · 2013 [cited by applicant]
WO WO2013061163A2 · 2013 [cited by applicant]
WO WO2013078375A2 · 2013 [cited by applicant]
WO WO2013172537A1 · 2013 [cited by applicant]
WO WO2014114303A1 · 2014 [cited by applicant]
WO WO2014114660A1 · 2014 [cited by applicant]
WO WO2014116865A1 · 2014 [cited by applicant]
WO WO2014159247A1 · 2014 [cited by applicant]
WO WO2016025692A1 · 2016 [cited by applicant]
WO WO2016050822A2 · 2016 [cited by applicant]
WO WO2017055612A1 · 2017 [cited by applicant]
WO WO2017176813A1 · 2017 [cited by applicant]
WO WO2018035408A1 · 2018 [cited by applicant]
WO WO2018195110A1 · 2018 [cited by applicant]
WO WO2019060918A1 · 2019 [cited by applicant]
WO WO2019067587A1 · 2019 [cited by applicant]
WO WO2021007110A1 · 2021 [cited by applicant]
WO WO2021055880A1 · 2021 [cited by applicant]
WO WO2021231887A1 · 2021 [cited by applicant]
Extended European Search Report, mailed Sep. 30, 2016, in connection with Application No. EP 14776090.4. [cited by applicant]
International Search Report and Written Opinion, mailed Aug. 22, 2014, in connection with Application No. PCT/US2014/022670. [cited by applicant]
International Preliminary Report on Patentability, mailed Sep. 24, 2015, in connection with Application No. PCT/US2014/022670. [cited by applicant]
International Search Report and Written Opinion, mailed Sep. 21, 2016, in connection with Application No. PCT/US2016/034738. [cited by applicant]
International Preliminary Report on Patentability, mailed Dec. 14, 2017, in connection with Application No. PCT/US2016/034738. [cited by applicant]
Supplementary Partial European Search Report, mailed Oct. 18, 2019, in connection with Application No. EP 17779695.0. [cited by applicant]
Extended European Search Report, mailed Jan. 7, 2020, in connection with Application No. EP 17779695.0. [cited by applicant]
International Search Report and Written Opinion, mailed Jul. 7, 2017, in connection with Application No. PCT/US2017/026020. [cited by applicant]
International Preliminary Report on Patentability, mailed Oct. 18, 2018, in connection with Application No. PCT/US2017/026020. [cited by applicant]
Extended European Search Report, mailed Dec. 17, 2020, in connection with Application No. EP 18786964.9. [cited by applicant]
International Search Report and Written Opinion, mailed Jul. 27, 2018, in connection with Application No. PCT/US2018/028015. [cited by applicant]
International Preliminary Report on Patentability, mailed Oct. 31, 2019, in connection with Application No. PCT/US2018/028015. [cited by applicant]
Extended European Search Report, mailed Nov. 26, 2021, in connection with Application No. EP 18860923.4. [cited by applicant]
International Search Report and Written Opinion, mailed Jan. 15, 2019, in connection with Application No. PCT/US2018/052913. [cited by applicant]
International Preliminary Report on Patentability, mailed Apr. 9, 2020, in connection with Application No. PCT/US2018/052913. [cited by applicant]
Extended European Search Report, mailed Jun. 11, 2021, in connection with Application No. EP 18859783.5. [cited by applicant]
International Search Report and Written Opinion, mailed Dec. 6, 2018, in connection with Application No. PCT/US2018/052745. [cited by applicant]
International Preliminary Report on Patentability, mailed Apr. 9, 2020, in connection with Application No. PCT/US2018/052745. [cited by applicant]
International Search Report and Written Opinion, mailed Dec. 31, 2020, in connection with Application No. PCT/US2020/051670. [cited by applicant]
International Preliminary Report on Patentability, mailed Apr. 7, 2022, in connection with Application No. PCT/US2020/051670. [cited by applicant]
Invitation to Pay Additional Fees, mailed Feb. 9, 2021, in connection with Application No. PCT/US2020/054976. [cited by applicant]
International Search Report and Written Opinion, mailed Apr. 23, 2021, in connection with Application No. PCT/US2020/054976. [cited by applicant]
International Preliminary Report on Patentability, mailed Apr. 21, 2022, in connection with Application No. PCT/US2020/054976. [cited by applicant]
[No Author Listed] Amersham ECL Western Blotting Detection Reagent. Retrieved from the internet under https://www.cytivalifesciences.com/en/us/shop/protein-analysis/blotting-and-detection/blotting-standards-and-reagents… [cited by applicant]
[No Author Listed] EBNA1—Epstein-Barr nuclear antigen 1—Epstein-Barr virus (strain GD1) (HHV-4)—EBNA1 gene & protein, Jan. 2018. 2018. Retrieved from the internet under https://www.uniprot.org/uniprot/Q3KSS4 on Sep. 12,… [cited by applicant]
[No Author Listed], Abstracts. Medizinische Genetik, Berufsverband Nedizinische Genetik, Muchen, DE. Medgen. Mar. 4, 2016; 28(1):84-232. DOI: 10.1007/s11825-016-0083-5. [cited by applicant]
Ash et al., Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. Feb. 20, 2013;77(4):639-46. doi: 10.1016/j.neuron.2013.02.004. Epub Feb. 12, 2013. [cited by applicant]
Ashizawa et al., GGCCTG repeats put a hex on Purkinje cells and motor neurons in SCA36. Neurology. Jul. 24, 2012;79(4):302-3. doi: 10.1212/WNL.0b013e31826043d9. Epub Jun. 27, 2012. [cited by applicant]
Ayhan et al., SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. EMBO J. Oct. 1, 2018;37(19). pii: e99023. doi: 10.15252/embj.201899023. Epub Sep. 11, 2018. [cited by applicant]
Baboonian et al., Cross reaction of antibodies to a glycine/alanine repeat sequence of Epstein-Barr virus nuclear antigen-1 with collagen, cytokeratin, and actin. Ann Rheum Dis. Nov. 1991;50(11):772-5. [cited by applicant]
Bae et al., Antibody-aided clearance of extracellular a-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. Sep. 26, 2012;32(39):13454-69. [cited by applicant]
Bañez-Coronel et al., A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet. 2012;8(2):e1002481. doi: 10.1371/journal.pgen.1002481. Epub Feb. 23, 2012. [cited by applicant]
Bañez-Coronel et al., RAN Translation in Huntington Disease. Neuron. Nov. 18, 2015;88(4):667-77. doi: 10.1016/j.neuron.2015.10.038. [cited by applicant]
Batra et al., Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum Mol Genet. Apr. 15, 2010;19(R1):R77-82. doi: 10.1093/hmg/ddq132. Epub Apr. 4, 2010. [cited by applicant]
Carroll et al., Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. Mol Ther. Dec. 2011;19(12):2178-… [cited by applicant]
Chen et al., Functional genomics in [cited by applicant]
Cleary et al., Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet. Oct. 15, 2013;22(R1):R45-51. doi: 10.1093/hmg/ddt371. Epub Aug. 4, 2013. [cited by applicant]
Donnelly et al., RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. Oct. 16, 2013;80(2):415-28. doi: 10.1016/j.neuron.2013.10.015. [cited by applicant]
Duan et al., Generation of polyclonal antiserum for the detection of methylarginine proteins. J Immunol Methods. Mar. 30, 2007;320(1-2):132-42. Epub Feb. 6, 2007. [cited by applicant]
Duellman et al., Antigen-binding properties of monoclonal antibodies reactive with EBNA1 and use in immunoaffinity chromatography. PLoS One. 2009;4(2):e4614. doi: 10.1371/journal.pone.0004614. Epub Feb. 26, 2009. [cited by applicant]
Gkogkas et al., Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep. Dec. 11, 2014;9(5):1742-1755. doi: 10.1016/j.celrep.2014.10.064. Epub Nov. 26, 2… [cited by applicant]
Gómez-Tortosa et al., C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology. Jan. 22, 2013;80(4):366-70. doi: 10.1212/WNL.0b013e31827f08ea. Epub Jan. 2, 2013. [cited by applicant]
Hock et al., Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. May 22, 2003;38(4):547-54. [cited by applicant]
Jin et al., Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics. Neuromolecular Med. Dec. 2016;18(4):581-592. doi: 10.1007/s12017-016-8412-z. Epub… [cited by applicant]
Kearse et al., CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. Mol Cell. Apr. 21, 2016;62(2):314-322. doi: 10.1016/j.molcel.2016.02.034. Epu… [cited by applicant]
Leitman et al., ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin. PLoS One. Mar. 3, 2014;9(3):e90803. doi: 10.1371/journal.pone.0090803. [cited by applicant]
Ma et al., Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci Lett. Jan. 10, 2007;411(2):98-103. doi: 10.1016/j.neulet.2006.10.039. Epub Nov. 15, 2006. [cited by applicant]
Mirkin, Expandable DNA repeats and human disease. Nature. Jun. 21, 2007;447(7147):932-40. doi: 10.1038/nature05977. [cited by applicant]
Mori et al., The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. Mar. 15, 2013;339(6125):1335-8. doi: 10.1126/science.1232927. Epub Feb. 7, 2013. Supplementary inform… [cited by applicant]
Satoh et al., Dystrophic neurites express C9orf72 in Alzheimer's disease brains. Alzheimers Res Ther. Aug. 16, 2012;4(4):33. doi: 10.1186/alzrt136. 13 pages. [cited by applicant]
Sha et al., Treatment implications of C9ORF72. Alzheimer's Res Ther. Nov. 27, 2012;4(6):46. doi: 10.1186/alzrt149. eCollection 2012. [cited by applicant]
Shoesmith et al., Amyotrophic lateral sclerosis: update for family physicians. Can Fam Physician. Dec. 2006;52(12):1563-9. [cited by applicant]
Trouth et al., Myasthenia gravis: a review. Autoimmune Dis.;2012:874680. doi: 10.1155/2012/874680. Epub Oct. 31, 2012. [cited by applicant]
Vaughn et al., Inhibition of PKR protects against tunicamycin-induced apoptosis in neuroblastoma cells. Gene. Feb. 15, 2014;536(1):90-6. doi: 10.1016/j.gene.2013.11.074. Epub Dec. 14, 2013. [cited by applicant]
Wang et al., Comparative Analysis of VOCs in Exhaled Breath of Amyotrophic Lateral Sclerosis and Cervical Spondylotic Myelopathy Patients. Sci Rep. 2016;6:26120. Published May 23, 2016. doi: 10.1038/srep26120. [cited by applicant]
Welnowska et al., Translation of viral mRNA without active eIF2: the case of picornaviruses. PLoS One. 2011;6(7):e22230. doi: 10.1371/journal.pone.0022230. Epub Jul. 14, 2011. [cited by applicant]
Wojciechowska et al., RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders. Nucleic Acids Res. Oct. 29, 2014;42(19):11849-64. doi: 10.1093/nar/gku794. Epub… [cited by applicant]
Xiao et al., Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol. Oct. 2015;78(4):568-83. doi: 10.1002/ana.24469. Epub Aug. 29, 2015. [cited by applicant]
Yanagisawa et al., Protein Binding of a DRPLA Family Through Arginine-Glutamic Acid Dipeptide repeats is Enhanced by Extended polyglutamine. Human Molecular Genetics. 2000;9(9):1433-1442. [cited by applicant]
Yu et al., Developing therapeutic antibodies for neurodegenerative disease. Neurotherapeutics. Jul. 2013;10(3):459-72. doi: 10.1007/s13311-013-0187-4. [cited by applicant]
Zhang et al., Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 2014;128:505-24. [cited by applicant]
Zhou et al., Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins. EMBO Mol Med. May 2017;9(5):687-702. doi: 10.15252/emmm.201607054. [cited by applicant]
Zu et al., RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. Dec. 17, 2013;110(51):E4968-77. doi: 10.1073/pnas.1315438110. Epub Nov. 18, 2013. [cited by applicant]
Extended European Search Report, mailed Oct. 4, 2023, in connection with application No. EP 20865149.7. [cited by applicant]
Invitation to Pay Additional Fees, mailed Nov. 30, 2020, in connection with Application No. PCT/US2020/051671. [cited by applicant]
International Search Report and Written Opinion, mailed Feb. 9, 2021, in connection with Application No. PCT/US2020/051671. [cited by applicant]
International Preliminary Report on Patentability, mailed Mar. 31, 2022, in connection with Application No. PCT/US2020/051671. [cited by applicant]
Extended European Search Report, mailed Aug. 25, 2023, in connection with Application No. EP 20869039.6. [cited by applicant]
Extended European Search Report, mailed Oct. 4, 2023, in connection with application No. EP 20874343.5. [cited by applicant]
Invitation to Pay Additional Fees, mailed Mar. 30, 2023, in connection with Application No. PCT/US2022/051530. [cited by applicant]
International Search Report and Written Opinion, mailed May 25, 2023, in connection with Application No. PCT/US2022/051530. [cited by applicant]
International Search Report and Written Opinion, mailed Jul. 19, 2023, in connection with Application No. PCT/US2023/063328. [cited by applicant]
Bando et al., Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease. Neurochem Int. Jan. 2005;46(1):11-8. doi: 10.1016/j.neuint.20… [cited by applicant]
Bañez-Coronel et al., Repeat-associated non-AUG (RAN) translation: insights from pathology. Lab Invest. Jul. 2019;99(7):929-942. doi: 10.1038/s41374-019-0241-x. Epub Mar. 27, 2019. [cited by applicant]
Bañez-Coronel et al., Sense and antisense RAN proteins in the CAG•CTG polyglutamine spinocerebellar ataxias. International Congress for Ataxia Research. Abstract ID 271. Nov. 1-4, 2022. 1 page. [cited by applicant]
Barzilai et al., Metformin as a Tool to Target Aging. Cell Metab. Jun. 14, 2016;23(6):1060-1065. doi: 10.1016/j.cmet.2016.05.011. [cited by applicant]
Benkirane et al., Oncogenic potential of TAR RNA binding protein TRBP and its regulatory interaction with RNA-dependent protein kinase PKR. EMBO J. Feb. 3, 1997;16(3):611-24. doi: 10.1093/emboj/16.3.611. [cited by applicant]
Brooks et al., Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease. Trends Neurosci. Oct. 1995;18(10):459-61. doi: 10.1016/0166-2236(95)94497-s. [cited by applicant]
Castelli et al., Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders. Biochem Soc Trans. Apr. 30, 2021;49(2):775-792. doi: 10.1042/BST20200690. [cited by applicant]
Chen et al., Antidiabetic drug metformin (Glucophage [cited by applicant]
Cheng et al., C9ORF72 GGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat Commun. Jan. 4, 2018;9(1):51. doi: 10.1038/s41467-017-02495-z. [cited by applicant]
Cleary et al., New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev. Jun. 2017;44:125-134. doi: 10.1016/j.gde.2017.03.006. Epub Mar. 30, 2017. Author Manuscript, 18 pages. [cited by applicant]
Cleary et al., Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev. Jun. 2014;26:6-15. doi: 10.1016/j.gde.2014.03.002. Epub May 22, 2014. Author Manuscript,… [cited by applicant]
Davidkin et al., Persistence of anti-mumps virus antibodies after a two-dose MMR vaccination. A nine-year follow-up. Vaccine. Nov. 1995;13(16):1617-22. doi: 10.1016/0264-410x(95)00064-8. [cited by applicant]
Foretz et al., Metformin: from mechanisms of action to therapies. Cell Metab. Dec. 2, 2014;20(6):953-66. doi: 10.1016/j.cmet.2014.09.018. Epub Oct. 30, 2014. [cited by applicant]
Gantois et al., Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med. Jun. 2017;23(6):674-677. doi: 10.1038/nm.4335. Epub May 15, 2017. [cited by applicant]
Gray et al., Comparability of serum prostate-specific antigen measurement between the Roche Diagnostics Elecsys 2010 and the Abbott Architect i2000. Ann Clin Biochem. May 2004;41(Pt 3):207-12. doi: 10.1258/0004563043230… [cited by applicant]
Green et al., RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun. Dec. 8, 2017;8(1):2005. doi: 10.1038/s41467-017-02200-0. [cited by applicant]
Guerra et al., Human gene profiling in response to the active protein kinase, interferon-induced serine/threonine protein kinase (PKR), in infected cells. Involvement of the transcription factor ATF-3 In PKR-induced apo… [cited by applicant]
Jawaid et al., ALS disease onset may occur later in patients with pre-morbid diabetes mellitus. Eur J Neurol. May 2010;17(5):733-9. doi: 10.1111/j.1468-1331.2009.02923.x. Epub Jan. 13, 2010. [cited by applicant]
Kioumourtzoglou et al., Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study. JAMA Neurol. Aug. 2015;72(8):905-11. doi: 10.1001/jamaneurol.2015.0910. Author Manuscript, 15… [cited by applicant]
Koide et al., Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. Jan. 1994;6(1):9-13. doi: 10.1038/ng0194-9. [cited by applicant]
Koob et al., An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. Apr. 1999;21(4):379-84. doi: 10.1038/7710. [cited by applicant]
Liu et al., C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. May 4, 2016;90(3):521-34. doi: 10.1016/j.neuron.2016.04.005. Epub Apr. 21, 2016. [cited by applicant]
Memmott et al., Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res (Phila). Sep. 2010;3(9):1066-76. doi: 10.1158/1940-6207.CAPR-10-0055. Epub Sep. 1, 2010. [cited by applicant]
Moon et al., Neuronal Regulation of eIF2α Function in Health and Neurological Disorders. Trends Mol Med. Jun. 2018;24(6):575-589. doi: 10.1016/j.molmed.2018.04.001. Epub Apr. 30, 2018. [cited by applicant]
Nguyen et al., Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease. Annu Rev Neurosci. Jul. 8, 2019;42:227-247. doi: 10.1146/annurev-neuro-070918-050405. Epub Mar. 25, 20… [cited by applicant]
Pakos-Zebrucka et al., The integrated stress response. EMBO Rep. Oct. 2016;17(10):1374-1395. doi: 10.15252/embr.201642195. Epub Sep. 14, 2016. [cited by applicant]
Park et al., TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR. Proc Natl Acad Sci U S A. May 24, 1994;91(11):4713-7. doi: 10.1073/pnas.91.11.4713. [cited by applicant]
Peel et al., Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue. Hum Mol Genet. Jul. 15, 2001;10(15):1531-8. doi: 10.1093/hmg/1… [cited by applicant]
Perez et al., CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. EMBO Mol Med. Nov. 8, 2021;13(11):e14095. doi: 10.15252/emmm.202114095. Epub Oct. 11, 2021. [cited by applicant]
Sonenberg et al., Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. Feb. 20, 2009;136(4):731-45. doi: 10.1016/j.cell.2009.01.042. [cited by applicant]
Soragni et al., Repeat-Associated Non-ATG (RAN) Translation in Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci. Apr. 1, 2018;59(5):1888-1896. doi: 10.1167/iovs.17-23265. [cited by applicant]
Taylor et al., Decoding ALS: from genes to mechanism. Nature. Nov. 10, 2016;539(7628):197-206. doi: 10.1038/nature20413. Author Manuscript, 28 pages. [cited by applicant]
Tian et al., Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA. Jan. 2000;6(1):79-87. doi: 10.1017/s1355838200991544. [cited by applicant]
Todd et al., CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron. May 8, 2013;78(3):440-55. doi: 10.1016/j.neuron.2013.03.026. Epub Apr. 18, 2013. Erratum in: Neuron.… [cited by applicant]
Todd et al., Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions. J Neurochem. Aug. 2016;138 Suppl 1:145-62. doi: 10.1111/jnc.13623. Epub Jun. 15, 2016. [cited by applicant]
Tsuji, S., Dentatorubral-pallidoluysian atrophy. Handb Clin Neurol. 2012; 103:587-94. doi: 10.1016/B978-0-444-51892-7.00041-3. [cited by applicant]
Vishwakarma et al., Current molecular insight to reveal the dynamics of CAG repeating units in spinocerebellar ataxia. Intractable Rare Dis Res. May 2018;7(2):79-86. doi: 10.5582/irdr.2018.01039. [cited by applicant]
Wieben et al., Amplification-free long-read sequencing of TCF4 expanded trinucleotide repeats in Fuchs Endothelial Corneal Dystrophy. PLoS One. Jul. 5, 2019;14(7):e0219446. doi: 10.1371/journal.pone.0219446. [cited by applicant]
Zhu et al., Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell. Dec. 9, 2011;147(6):1384-96. doi: 10.1016/j.cell.2011.11.029. [cited by applicant]
Zu et al., Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proc Natl Acad Sci U S A. Aug. 4, 2020;117(31):18591-18599. doi: 10.1073/pnas.2005748117. Epub Jul. 20, 20… [cited by applicant]
Zu et al., Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. Jan. 4, 2011;108(1):260-5. doi: 10.1073/pnas.1013343108. Epub Dec. 20, 2010. [cited by applicant]
Zu et al., RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron. Sep. 13, 2017;95(6):1292-1305.e5. doi: 10.1016/j.neuron.2017.08.039. [cited by applicant]
International Preliminary Report on Patentability, mailed Jun. 13, 2024, in connection with Application No. PCT/US2022/051530. [cited by applicant]
International Preliminary Report on Patentability, mailed Sep. 12, 2024, in connection with Application No. PCT/US2023/063328. [cited by applicant]
[No Author Listed] CRC group Top> L. K. Housing> Query, after sampling and sampling, was conducted, kept still in whole blood ; CRC Corporation, Jun. 30, 2013. https://web.archive.org/web/20130630024235/http://www.crc-g… [cited by applicant]
Alaoui-Ismaili et al., Design of second generation therapeutic recombinant bone morphogenetic proteins. Cytokine Growth Factor Rev. Oct.-Dec. 2009;(5-6):501-7. doi: 10.1016/j.cytogfr.2009.10.001. Epub Nov. 11, 2009. [cited by applicant]
Asokan et al., The AAV vector toolkit: poised at the clinical crossroads. Mol Ther. Apr. 2012;20(4):699-708. doi: 10.1038/mt.2011.287. Epub Jan. 24, 2012. [cited by applicant]
Atwood et al., A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis. J Alzheimers Dis. 2015;47(1):33-47. doi: 10.3233/JAD-143210. [cited by applicant]
Brujin et al., Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004;27:723-49. doi: 10.1146/annurev.neuro.27.070203.144244. [cited by applicant]
Burgess et al., Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single … [cited by applicant]
Cendelin et al., Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications. Cerebellum. Jun. 2022;21(3):452-481. doi: 10.1007/s12311-021-01311-1. Epub Aug. 10,… [cited by applicant]
Cui et al., Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Front Neurosci. Jun. 4, 2024;18:1422442. doi: 10.3389/fnins.2024.1422442. [cited by applicant]
Gendron et al., Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol. Oct. 2015;130(4):559-73. doi: 10.1007/s00401-015-1474-4. Ep… [cited by applicant]
Gendron et al., Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med. Mar. 29, 2017;9(383):eaai7866. doi: 10.1126/scitranslmed.aai7866. [cited by applicant]
Guo et al., Protein tolerance to random amino acid change. Proc Natl Acad Sci U S A. Jun. 22, 2004;101(25):9205-10. doi: 10.1073/pnas.0403255101. Epub Jun. 14, 2004. [cited by applicant]
Guo et al., RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies. Curr Opin Neurobiol. Feb. 2022;72:160-170. doi: 10.1016/j.conb.2021.11.001. Epub Dec. 22, 2021. [cited by applicant]
Henstridge et al., Beyond the neuron-cellular interactions early in Alzheimer disease pathogenesis. Nat Rev Neurosci. Feb. 2019;20(2):94-108. doi: 10.1038/s41583-018-0113-1. [cited by applicant]
Ju et al., A yeast model of FUS/TLS-dependent cytotoxicity. PLoS Biol. Apr. 2011;9(4):e1001052. doi: 10.1371/journal.pbio.1001052. Epub Apr. 26, 2011. [cited by applicant]
Lagier-Tourenne et al., TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet. Apr. 15, 2010;19(R1):R46-64. doi: 10.1093/hmg/ddq137. Epub Apr. 15, 2010. [cited by applicant]
Pawson et al., Assembly of cell regulatory systems through protein interaction domains. Science. Apr. 18, 2003;300(5618):445-52. doi: 10.1126/science.1083653. [cited by applicant]
Ranganathan et al., Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia. Front Neurosci. Jul. 7, 2020;14:684. doi: 10.3389/fnins.2020.00684. [cited by applicant]
Rothstein, Therapeutic horizons for amyotrophic lateral sclerosis. Curr Opin Neurobiol. Oct. 1996;6(5):679-87. doi: 10.1016/s0959-4388(96)80103-6. [cited by applicant]
Sarter, Animal cognition: defining the issues. Neurosci Biobehav Rev. Nov. 2004;28(7):645-50. doi: 10.1016/j.neubiorev.2004.09.005. [cited by applicant]
Swerdlow, Pathogenesis of Alzheimer's disease. Clin Interv Aging. 2007;2(3):347-59. [cited by applicant]
Tandon et al., Polyglutamine disorders: Pathogenesis and potential drug interventions. Life Sci. May 1, 2024;344:122562. doi: 10.1016/j.lfs.2024.122562. Epub Mar. 14, 2024. [cited by applicant]
Tayebati, Animal models of cognitive dysfunction. Mech Ageing Dev. Feb. 2006; 127(2):100-8. doi: 10.1016/j.mad.2005.09.026. Epub Nov. 15, 2005. [cited by applicant]
William et al., Old friends on new paths: metformin as an early phase treatment in Huntington's Disease?, Medizinische Genetik, 28, pp. 215-216, Mar. 4, 2016 (Mar. 4, 2016) (Abstract). [cited by applicant]
Williams et al., CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun. Apr. 15, 2016;7:11253. doi: 10.1038/ncomms11253. [cited by applicant]
Anger, Animal test systems to study behavioral dysfunctions of neurodegenerative disorders. Neurotoxicology. 1991 Fall;12(3):403-13. [cited by applicant]
Murase et al., Drug Discovery Research Toward the Small Molecular Therapeutic Agents for Repeat Expansion Diseases, Nagasaki International University Review, Mar. 2022, vol. 22, pp. 177-185. [cited by applicant]