Patents Assigned to The Whitehead Institute for Biomedical Research
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Patent number: 11092602Abstract: In some aspects, the disclosure provides methods of modulating the level of proteasome inhibitor resistance of a cell, the methods comprising manipulating the level of expression or activity of a subunit of the 19S proteasome in the cell. In some aspects, cells in which the level of a 19S subunit is modulated, e.g., reduced, are provided. In some aspects, methods of identifying agents that reduce proteasome inhibitor resistance are provided. In some aspects, methods of classifying cancers according to predicted proteasome inhibitor resistance are provided. In some aspects, methods of killing or inhibiting proliferation of cancer cells, e.g., proteasome inhibitor resistant cancer cells, are provided. In some aspects, methods of treating cancer, e.g., proteasome inhibitor resistant cancer, are provided.Type: GrantFiled: July 6, 2016Date of Patent: August 17, 2021Assignees: Whitehead Institute for Biomedical Research, The Brigham and Women's Hospital, Inc.Inventors: Peter Tsvetkov, Sandro Santagata, Susan Lindquist
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Publication number: 20210230538Abstract: The present disclosure provides compounds of any one of Formulae (A) to (L). The present disclosure also provides compositions, uses, and methods that include or involve a compound described herein, a serine/threonine-protein kinase B-Raf (BRAF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor 1 (VEGFR1) inhibitor, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, or a combination thereof. The compounds, compositions, uses, and methods are useful in changing the pluripotency state of a vertebrate cell to a more nave state.Type: ApplicationFiled: October 15, 2020Publication date: July 29, 2021Applicants: Whitehead Institute for Biomedical Research, Dana-Farber Cancer Institute, Inc.Inventors: Thorold W. Theunissen, Nathanael S. Gray, Rudolf Jaenisch
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Patent number: 11047848Abstract: In some aspects, a cross-species platform useful for drug discovery in neurodegenerative diseases is described.Type: GrantFiled: March 17, 2014Date of Patent: June 29, 2021Assignee: Whitehead Institute for Biomedical ResearchInventors: Susan L. Lindquist, Vikram Khurana, Chee-Yeun Chung
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Patent number: 11041161Abstract: Metabolic flux biosensors are provided herein, as are related compositions and methods useful for, inter alia, identifying factors which increase the production of metabolites and/or end products of metabolic pathways, and for the production of inter alia, metabolites and/or end products of metabolic pathways.Type: GrantFiled: January 8, 2015Date of Patent: June 22, 2021Assignees: Whitehead Institute for Biomedical Research, Massachusetts Institute of TechnologyInventors: Jose Luis Avalos, Gerald Fink, Gregory Stephanopoulos
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Patent number: 11028185Abstract: Methods and reagents for the installation of click chemistry handles on target proteins are provided, as well as modified proteins comprising click chemistry handles. Further, chimeric proteins, for example, bi-specific antibodies, that comprise two proteins conjugated via click chemistry, as well as methods for their generation and use are disclosed herein.Type: GrantFiled: September 24, 2018Date of Patent: June 8, 2021Assignee: Whitehead Institute for Biomedical ResearchInventors: Hidde L. Ploegh, Martin D. Witte, Nicholas C. Yoder
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Patent number: 10941429Abstract: Disclosed are methods, compositions, proteins, nucleic acids, cells, vectors, compounds, reagents, and systems for the preparation of kavalactones, flavokavains, and kavalactone and flavokavain biosynthetic intermediates using enzymes expressed in heterologous host cells, such as microorganisms or plants, or using in vitro enzymatic reactions. This invention also provides for the expression of the enzymes by recombinant cell lines and vectors. Furthermore, the enzymes can be components of constructs such as fusion proteins. The kavalactones produced can be utilized to treat anxiety disorder, insomnia, and other psychological and neurological disorders. The flavokavains produced can be utilized to treat various cancers including colon, bladder, and breast cancers.Type: GrantFiled: January 16, 2019Date of Patent: March 9, 2021Assignee: Whitehead Institute for Biomedical ResearchInventors: Tomás Pluskal, Jing-Ke Weng
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Publication number: 20200384137Abstract: The present invention, in some aspects, provides methods, reagents, compositions, and kits for the radiolabeling of proteins, for example, of proteins useful for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) (e.g., for diagnostic and therapeutic applications), using sortase-mediated transpeptidation reactions. Some aspects of this invention provide methods for the conjugation of an agent, for example, a radioactive agent or molecule to diagnostic or therapeutic peptides or proteins. Compositions comprising sortagged, radiolabeled proteins as well as reagents for generating radiolabeled proteins are also provided. Kits comprising reagents useful for the generation of radiolabeled proteins are provided, as are precursor proteins that comprise a sortase recognition motif.Type: ApplicationFiled: January 8, 2020Publication date: December 10, 2020Applicants: Whitehead Institute for Biomedical Research, The General Hospital CorporationInventors: Mohammad Rashidian, Hidde L. Ploegh, Ralph Weissleder, Edmund J. Keliher
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Publication number: 20200375996Abstract: A method for treating neurodegenerative disease in a subject in need thereof by administering to the subject an effective amount of a Nedd4 activator as described herein.Type: ApplicationFiled: December 14, 2016Publication date: December 3, 2020Applicants: D.E. Shaw Research, LLC, WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCHInventors: Yibing SHAN, Venkat MYSORE, Susan LINDQUIST, Dan TARDIFF, Srividya CHANDRAMOULI
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Patent number: 10745744Abstract: The disclosed Hi-C protocol can identify genomic loci that are spatially co-located in vivo. These spatial co-locations may include, but are not limited to, intrachromosomal interactions and/or interchromosomal interactions. Hi-C techniques may be applied to many different scales of interest. For example, on a large scale, Hi-C techniques can be used to identify long-range interactions between distant genomic loci.Type: GrantFiled: June 15, 2017Date of Patent: August 18, 2020Assignees: University of Massachusetts, Massachusetts Institute of Technology, President and Fellows of Harvard College, Whitehead Institute for Biomedical ResearchInventors: Job Dekker, Erez Lieberman Aiden, Nynke Van Berkum, Andreas Gnirke, Eric Lander, Chad Nusbaum, Louise Williams, Alexandre Melnikov, Georgia Giannoukos
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Publication number: 20200206269Abstract: Multi-step methods for the in vitro production of enucleated red blood cells and the enucleated red blood cells thus prepared are provided. Such enucleated red blood cells may express fusion proteins comprising an antigen binding protein which allows the red blood cell to bind a toxin or an antigen of a pathogen. Also described herein are methods for neutralizing a toxin or pathogen in a subject by administering enucleated red blood cells that express any of the fusion proteins provided herein.Type: ApplicationFiled: August 22, 2018Publication date: July 2, 2020Applicants: Whitehead Institute for Biomedical Research, Trustees of Tufts CollegeInventors: Harvey Lodish, Nai-Jia Huang, Novalia Pishesha, Hidde L. Ploegh, Charles Shoemaker
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Patent number: 10633656Abstract: Double-stranded RNA (dsRNA) induces sequence-specific post-transcriptional gene silencing in many organisms by a process known as RNA interference (RNAi). Using a Drosophila in vitro system, we demonstrate that 19-23 nt short RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III-like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3? ends mediate efficient target RNA cleavage in the lysate, and the cleavage site is located near the center of the region spanned by the guiding siRNA. Furthermore, we provide evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by the produced siRNP complex.Type: GrantFiled: December 22, 2016Date of Patent: April 28, 2020Assignees: MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN E.V., MASSACHUSETTS INSTITUTE OF TECHNOLOGY, Whitehead Institute for Biomedical Research, UNIVERSITY OF MASSACHUSETTSInventors: Thomas Tuschl, Sayda Mahgoub Elbashir, Winfried Lendeckel
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Publication number: 20200085817Abstract: Potassium chloride cotransporter-2 (KCC2) plays a critical role in brain function, and deficiency in KCC2 has been linked to neurological diseases, psychiatric disorders, and central nervous system injuries. In particular, Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the X-linked gene Methyl CpG binding Protein 2 (MECP2), has been linked to deficits in KCC2. The disclosure reports the use of CRISPR/Cas9 genome-editing technology to generate stem cell-derived, genetically defined KCC2 reporter human neurons for large-scale compound screening. This screening platform has been utilized to identify a number of small molecule compounds that are capable of enhancing KCC2 expression in both wild-type and RTT neurons, as well as organotypical brain slices cultured from wild-type mice.Type: ApplicationFiled: May 22, 2018Publication date: March 19, 2020Applicant: Whitehead Institute for Biomedical ResearchInventors: Rudolf Jaenisch, Xin Tang
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Publication number: 20200069736Abstract: Methods for the in vitro production of enucleated red blood cells and the enucleated red blood cells thus prepared are provided. Such enucleated red blood cells may express a sortaggable surface protein, which allows for surface modification in the presence of a sortase. Also described herein are surface modified enucleated red blood cells, e.g., conjugated with an agent of interest such as a peptide, a detectable label, or a chemotherapeutic agent, and uses thereof in delivering the agent to a subject.Type: ApplicationFiled: September 16, 2019Publication date: March 5, 2020Applicant: Whitehead Institute for Biomedical ResearchInventors: Harvey Lodish, Hidde L. Ploegh, Hsiang-Ying Lee, Jiahai Shi, Lenka Hoffman, Novalia Pishesha
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Patent number: 10556024Abstract: The present invention, in some aspects, provides methods, reagents, compositions, and kits for the radiolabeling of proteins, for example, of proteins useful for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) (e.g., for diagnostic and therapeutic applications), using sortase-mediated transpeptidation reactions. Some aspects of this invention provide methods for the conjugation of an agent, for example, a radioactive agent or molecule to diagnostic or therapeutic peptides or proteins. Compositions comprising sortagged, radiolabeled proteins as well as reagents for generating radiolalebed proteins are also provided. Kits comprising reagents useful for the generation of radiolabeled proteins are provided, as are precursor proteins that comprise a sortase recognition motif.Type: GrantFiled: November 13, 2014Date of Patent: February 11, 2020Assignees: Whitehead Institute for Biomedical Research, The General Hospital CorporationInventors: Mohammad Rashidian, Hidde L. Ploegh, Ralph Weissleder, Edmund J. Keliher
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Patent number: 10548959Abstract: Compositions and methods for modified dendrimer nanoparticle (“MDNP”) delivery of therapeutic, prophylactic and/or diagnostic agent such as large repRNA molecules to the cells of a subject have been developed. MDNPs efficiently drive proliferation of antigen-specific T cells against intracellular antigen, and potentiate antigen-specific antibody responses. MDNPs can be multiplexed to deliver two or more different repRNAs to modify expression kinetics of encoded antigens and to simultaneous deliver repRNAs and mRNAs including the same UTR elements that promote expression of encoded antigens.Type: GrantFiled: September 23, 2016Date of Patent: February 4, 2020Assignees: Massachusetts Institute of Technology, Whitehead Institute for Biomedical ResearchInventors: Omar F. Khan, Jasdave S. Chahal, Daniel G. Anderson, Hidde Ploegh, Robert S. Langer, Tyler E. Jacks, David A. Canner
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Patent number: 10526651Abstract: Disclosed are compositions and methods for modulating expression of genes that function at the step of ER to Golgi trafficking. Compounds that modulate expression of these genes or activity of the encoded proteins can be used to inhibit alpha-synuclein mediated toxicity and used to treat or prevent synucleinopathies such as Parkinson's disease. Also disclosed are methods of identifying inhibitors of alpha-synuclein mediated toxicity.Type: GrantFiled: January 18, 2013Date of Patent: January 7, 2020Assignees: Whitehead Institute for Biomedical Research, The Curators of the University of MissouriInventors: Susan L. Lindquist, Aaron D. Gitler, Anil Cashikar, Antony A. Cooper, Cole M. Haynes
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Publication number: 20190359933Abstract: Non-genetically engineered mammalian cells modified by sortase-mediated conjugation of an agent thereto are provided. Methods of conjugating agents to non-genetically engineered mammalian cells using sortase are provided. Methods of using the cells, e.g., for diagnostic and/or therapeutic purposes, are provided.Type: ApplicationFiled: April 11, 2019Publication date: November 28, 2019Applicant: Whitehead Institute for Biomedical ResearchInventors: Lee Kim Swee, Hidde L. Ploegh
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Patent number: 10472625Abstract: The present invention relates to a Drosophila in vitro system which was used to demonstrate that dsRNA is processed to RNA segments 21-23 nucleotides (nt) in length. Furthermore, when these 21-23 nt fragments are purified and added back to Drosophila extracts, they mediate RNA interference in the absence of long dsRNA. Thus, these 21-23 nt fragments are the sequence-specific mediators of RNA degradation. A molecular signal, which may be their specific length, must be present in these 21-23 nt fragments to recruit cellular factors involved in RNAi. This present invention encompasses these 21-23 nt fragments and their use for specifically inactivating gene function. The use of these fragments (or chemically synthesized oligonucleotides of the same or similar nature) enables the targeting of specific mRNAs for degradation in mammalian cells, where the use of long dsRNAs to elicit RNAi is usually not practical, presumably because of the deleterious effects of the interferon response.Type: GrantFiled: October 16, 2015Date of Patent: November 12, 2019Assignees: Max-Planck-Gesellschaft Zur Förderung Der Wissenschaften E.V., Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research, University of MassachusettsInventors: Thomas Tuschl, Phillip D. Zamore, Phillip A. Sharp, David P. Bartel
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Patent number: 10471099Abstract: Methods for the in vitro production of enucleated red blood cells and the enucleated red blood cells thus prepared are provided. Such enucleated red blood cells may express a sortaggable surface protein, which allows for surface modification in the presence of a sortase. Also described herein are surface modified enucleated red blood cells, e.g., conjugated with an agent of interest such as a peptide, a detectable label, or a chemotherapeutic agent, and uses thereof in delivering the agent to a subject.Type: GrantFiled: May 9, 2014Date of Patent: November 12, 2019Assignee: Whitehead Institute for Biomedical ResearchInventors: Harvey Lodish, Hidde L. Ploegh, Hsiang-Ying Lee, Jiahai Shi, Lenka Hoffman, Novalia Pishesha
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Patent number: 10457917Abstract: The invention provides methods for reprogramming somatic cells to generate multipotent or pluripotent cells. Such methods are useful for a variety of purposes, including treating or preventing a medical condition in an individual. The invention further provides methods for identifying an agent that reprograms somatic cells to a less differentiated state.Type: GrantFiled: July 9, 2018Date of Patent: October 29, 2019Assignee: Whitehead Institute for Biomedical ResearchInventors: Rudolf Jaenisch, Konrad Hochedlinger