Children's Medical Center Corporation

Harvard College

The General Hospital Corporation

The United States of America, As Represented by the Secretary, Department of Health and Human Services

The General Hospital Corporation D/b/a Massachusetts General Hospital

Derrick J Rossi

Luigi Warren

David T Scadden

Rahul Palchaudhuri

Agnieszka D Czechowicz

Wataru Ebina

Kenneth R Chien

Lee L Rubin

Chad A Cowan

Morag Helen Stewart

Lior Zangi

Lance Davidow

Paula Gutierrez-Martinez

Kiran Musunuru

Leon M Ptaszek

Philip M Murphy

Oi-Lan Lui

Roi Gazit

Zhanzhuo Li

Kathy Oi-Lan Lui

Oi Lan Lui

Provided are methods and compositions conditioning a patient for an allogeneic transplantation, wherein the patient's hematopoietic stem cells (HSCs) are depleted with an HSC-depleting composition and the patient is then administered allogeneic cells selected from bone marrow cells, umbilical cord blood cells, hematopoietic stem and progenitor cells (HSPCs), peripheral blood CD34cells, and peripheral blood CD34and CD90cells; optionally the patient is also administered a medicament selected from the group consisting of a T-cell depleting or inhibiting antibody or antibody fragment, NK-cell depleting or inhibiting antibody or antibody fragment, immunosuppressive drug, and any combination thereof. The HSC-depleting composition comprises a compound selected from the group consisting of: an antibody or antibody fragment with specific binding affinity to a protein displayed at the HSC surface, a conjugate comprising an HSC-recognition molecule and a toxin, and any combination thereof.

Antibody-mediated conditioning with immunosuppression to enable allogeneic transplantation

Aspects of the invention described herein relate to synthetic, modified RNAs and their use in vivo to modulate gene expression. Aspects of the invention further relate to the use of these synthetic, modified RNAs in myocytes, cardiomyocytes, and tumors.

Efficient protein expression in vivo using modified RNA (mod-RNA)

Disclosed herein are non-myeloablative antibody-toxin conjugates and compositions that target cell surface markers, such as the CD34, CD45 or CD117 receptors, and related methods of their use to effectively conditioning a subject's tissues (e.g., bone marrow tissue) prior to engraftment or transplant. The compositions and methods disclosed herein may be used to condition a subject's tissues in advance of, for example, hematopoietic stem cell transplant and advantageously such compositions and methods do not cause the toxicities that are commonly associated with traditional conditioning methods.

Compositions and methods for non-myeloablative conditioning

Described herein are synthetic, modified RNAs for changing the phenotype of a cell, such as expressing a polypeptide or altering the developmental potential. Accordingly, provided herein are compositions, methods, and kits comprising synthetic, modified RNAs for changing the phenotype of a cell or cells. These methods, compositions, and kits comprising synthetic, modified RNAs can be used either to express a desired protein in a cell or tissue, or to change the differentiated phenotype of a cell to that of another, desired cell type.

Mammalian somatic cell with modified RNA encoding reprogramming factors

The methods and compositions described herein relate to producing, expanding, enriching, and/or maintaining hematopoietic stem cells ex vivo by treating the cells with an agent(s) that exhibits two or more activities selected from modulation of histone methylation; inhibition of TGFβ signaling; inhibition of p38 signaling; activation of canonical Wnt signaling; and modulation of histone acetylation. In some embodiments, the technology described herein relates to transplantation of hematopoietic stem cells.

Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance

Isolated mammalian somatic cells containing modified RNA encoding OCT4, SOX2, and KLF4

The methods and compositions described herein relate to producing, expanding, enriching, and/or maintaining hematopoietic stem cells ex vivo by treating the cells with an agent(s) that exhibits two or more activities selected from modulation of histone methylation; inhibition of TGF&#x3b2; signaling; inhibition of p38 signaling; activation of canonical Wnt signaling; and modulation of histone acetylation. In some embodiments, the technology described herein relates to transplantation of hematopoietic stem cells.

Sustained polypeptide expression from synthetic, modified RNAs and uses thereof

Disclosed herein are methods, compositions, and kits for high efficiency, site-specific genomic editing of cells for treating or preventing genetic blood disorders.

Therapeutic uses of genome editing with CRISPR/Cas systems

Aspects of the invention described herein relate to synthetic, modified RNAs and their use in vivo to modulate gene expression. Aspects of the invention further relate to the use of these synthetic, modified RNAs in myocytes, cardiomyoctes, and tumors.

Efficient protein expression in vivo using modified RNA (MOD-RNA)

Described herein are nucleic acid constructs, hematopoietic stem cell identifier animals, and methods of using thereof for isolating hematopoietic stem cell populations. Also provided are methods of using the identifier animals and cells isolated from them to screen for agents that affect the growth, proliferation, potency, expansion, or maintenance of the stem cells. Such agents can be used for promoting growth of stem cells in vitro or in vivo, and also for inhibiting cancer cells that have been determined to resemble a stem cell.

Hematopoietic stem cell specific reporter mouse and uses thereof

Disclosed herein are methods, compositions, and kits for high efficiency, site-specific genomic editing of cells.

Growing community of inventors

Newton, MA, United States of America

Derrick J Rossi