University of California

Procella Therapeutics Ab

Genentech, Inc.

The General Hospital Corporation

Other

Children's Medical Center Corporation

Centelion

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

Kenneth R Chien

William I Wood

Kathleen King

Joffre B Baker

Diane Pennica

Jonathan Clarke

Chuen Yan Leung

Ming Dong Zhou

John Ross, Jr

Derrick J Rossi

Xiaojun Lance Lian

Sylvia Evans

Ju Chen

Lior Zangi

Wataru Ebina

Jiejia Xu

Federica Santoro

Makoto Sahara

Leon M Ptaszek

Miia Lehtinen

Kylie Foo

Ronald Mark Evans

Patrick Benoit

Jerrold M Olefsky

Henry M Sucov

Chenleng Cai

Alessandra Moretti

Xin Jiang

Bertrand Schwartz

Didier Branellec

Kathy Oi Lan Lui

Jolanta Chmielowiec

Yibin Wang

Diane Pennice

Lisa Lesniewski

Kathy Oi-Lan Lui

Mohammad Pashmforoush

Oi-Lan Lui

Karl-Ludwig Laugwitz

Masahiko Hoshijma

Lei Bu

Yasuhiro Ikeda

Oi Lan Lui

The present invention provides NRP1 as a cell surface marker for isolating human cardiomyogenic ventricular progenitor cells (HVPs), in particular progenitor cells that preferentially differentiate into cardiac ventricular muscle cells. Additional HVP cell surface markers identified by single cell sequencing are also provided. The invention provides in vitro methods of the separation of NRP1+ ventricular progenitor cells, and the large scale expansion and propagation thereof. Large clonal populations of isolated NRP1+ ventricular progenitor cells are also provided. Methods of in vivo use of NRP1+ ventricular progenitor cells for cardiac repair or to improve cardiac function are also provided. Methods of using the NRP1+ ventricular progenitor cells for cardiac toxicity screening of test compounds are also provided.

Use of neuropilin-1 (NRP1) as a cell surface marker for isolating human cardiac ventricular progenitor cells

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)

The present invention provides genetic markers for identifying engraftable human cardiac ventricular progenitor cells. The engraftment markers of the invention include angiogenic markers and extracellular matrix markers. Human ventricular progenitor cells expressing these markers are capable of forming ventricular tissue in vivo that is vascularized and supported by an extracellular matrix. Methods of engrafting human cardiac ventricular progenitor cells by transplanting into a subject progenitor cells that express the engraftment markers are also provided.

Genetic markers for engraftment of human cardiac ventricular progenitor cells

The present invention provides methods for isolating human cardiac ventricular progenitor cells (HVPs), wherein cultures of day 5-7 cardiac progenitor cells are negatively selected for one or more first markers expressed on human pluripotent stem cells, such as TRA-1-60, to thereby isolate HVPs. The methods can further include positive selection for expression of a second marker selected from the group consisting of JAG1, FZD4, LIFR, FGFR3 and TNFSF9. Large populations, including clonal populations, of isolated HVPs that are first marker negative/second marker positive are also provided. Methods of in vivo use of the HVPs for cardiac repair or to improve cardiac function are also provided. Methods of using the HVPs for cardiac toxicity screening of test compounds are also provided.

Methods for isolating human cardiac ventricular progenitor cells

Use of Neuropilin-1 (NRP1) as a cell surface marker for isolating human cardiac ventricular progenitor cells

The present invention provides LIFR and FGFR3 as cell surface markers for isolating human cardiomyogenic ventricular progenitor cells, in particular progenitor cells that preferentially differentiate into cardiac ventricular muscle cells. Thus, the invention provides human ventricular progenitor (HVP) cells. The invention provides in vitro methods of the separation of Islet 1+ LIFR+ ventricular progenitor cells and/or Islet 1+/FGFR3+ ventricular progenitor cells and/or Islet 1+/LIFR+/FGFR3+ ventricular progenitor cells, and the large scale expansion and propagation thereof. Large clonal populations of isolated LIFR+ and/or FGFR3+ ventricular progenitor cells are also provided. Methods of in vivo use of LIFR+ and/or FGFR3+ ventricular progenitor cells for cardiac repair or to improve cardiac function are also provided. Methods of using the LIFR+ and/or FGFR3+ ventricular progenitor cells for cardiac toxicity screening of test compounds are also provided.

Use of LIFR or FGFR3 as a cell surface marker for isolating human cardiac ventricular progenitor cells

The present invention provides Jagged 1 and Frizzled 4 as cell surface markers for isolating human cardiomyogenic ventricular progenitor cells, in particular progenitor cells that preferentially differentiate into cardiac ventricular muscle cells. Thus, the invention provides human ventricular progenitor (HVP) cells. The invention provides in vitro methods of the separation of Islet 1+ Jagged 1+ ventricular progenitor cells and/or Islet 1+/Frizzled 4+ ventricular progenitor cells and/or Islet 1+/Jagged 1+/Frizzled 4+ ventricular progenitor cells, and the large scale expansion and propagation thereof. Large clonal populations of isolated Jagged 1+ and/or Frizzled 4+ventricular progenitor cells are also provided. Methods of in vivo use of Jagged 1+ and/or Frizzled 4+ ventricular progenitor cells for cardiac repair or to improve cardiac function are also provided. Methods of using the Jagged 1+ and/or Frizzled 4+ ventricular progenitor cells for cardiac toxicity screening of test compounds are also provided.

Use of jagged 1/frizzled 4 as a cell surface marker for isolating human cardiac ventricular progenitor cells

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)

The present invention relates to the generation of vascularized human heart tissue from human primordial Islet1-positive (ISL1+) progenitors, and more particularly the generation of vascularized human heart tissue from human primordial Islet1+ cardiovascular stem cells which are positive for markers ISL1+/NKX2.5&#x2212;/KDR&#x2212;. One aspect of the invention relates to isolation of human ISL1+ primordial cells from human pluripotent cells, such as human ES cells or other human pluripotent stem cell sources, wherein the human ISL1+ primordial cells can differentiate into three different lineages; cardiomyocyte lineages, endothelial lineages and smooth muscle lineages. Another aspect relates to use and implantation of the human primordial ISL1+ progenitors into an animal model to generate human vascularized heart tissue, and more particularly, the production of an in vivo humanized model of vascular disease. One embodiment relates to the use of an in vivo humanized model of vascular disease as an assay, for example to assess drug toxicity and/or identify agents which increase and decrease coronary blood flow to the human vascularized heart tissue. Another embodiment relates to the therapeutic use of human primordial ISL1+ progenitors, for example, in one embodiment the invention provides methods for the treatment cardiovascular disorders and/or congenital heart disease in a subject comprising transplanting into subjects vascularized human heart tissue generated from human ISL1+ progenitors.

Generation of vascularized human heart tissue and uses thereof

Provided are methods of treating insulin resistance or type II diabetes. Disrupting CAP in the macrophage can alter the inflammatory response associated with impaired insulin action and ultimately result in improved insulin action in target tissues. One aspect of the invention involves administering a CAP antagonist to a patient afflicted with insulin resistance or type II diabetes in an amount sufficient to improve insulin action in target tissues.

Diabetes treatment methods and drug targets therefor

The present invention provides in vitro methods of expansion and propagation of undifferentiated progenitor cells and more specifically undifferentiated progenitor cells containing Islet1, a marker apparently unique to proliferating cardiac stem cells. Methods are described for isolation of stem cell populations as well as for provoking expansion and propagation of undifferentiated progenitor cells without differentiation, to provide cardiac repair or improve cardiac function, for example.

Use of islet 1 as a marker for isolating or generating stem cells

Methods for the delivery of genes to improve cardiac function including the use of viral vectors, isolation of the heart from systemic circulation, and induction of hypothermia/cardiac arrest are described. The method results in high-level, long-term expression of reporter genes and enhanced cardiac function in hamster models of heart disease.

Methods for cardiac gene transfer

The invention relates to novel promoter sequences derived from a portion upstream of the coding sequence of the gene for the CARP protein (Cardiac Ankyrin Repeat Protein), and which are capable of controlling the level and the specificity of expression of a transgene in vivo in cardiac muscle cells. The invention thus describes novel compositions, constructs, vectors and their uses in vivo for the transfer and expression of a nucleic acid in vivo in cardiac muscle cells. The subject of the present invention is also the use of the promoter sequences for generating transgenic animals which constitute models for studying certain cardiac pathologies.

Sequences upstream of the CARP gene, vectors containing them and uses thereof

Growing community of inventors

Cambridge, MA, United States of America

Kenneth R Chien