Seattle Children's Hospital

University of California

Fred Hutchinson Cancer Center

David J Rawlings

Andrew M Scharenberg

Iram F Khan

Kamila Sabina Gwiazda

Hans-Peter Kiem

Kyle Jacoby

Olivier M Humbert

Karen Sommer

Yuchi Chiang Honaker

Christopher Lux

Sowmya Pattabhi

Michael C Jensen

Douglas C Saffran

Owen N Witte

Michael T Certo

Ryo Takeuchi

Richard A Gatti

Alexandra E Grier

Troy Torgerson

Swati Singh

Thor Wagner

Blythe Sather

Satoshi Tsukada

Carol Hsing Miao

Jaya Sahni

Samuel West

King Hung

Richard James

Helen H Chun

Shaun W Jackson

Chong Li

Methods, compositions, and systems for treating subject(s) in need of plasma Factor VIII, particularly a subject having preexisting anti-FVIII inhibitory antibodies, are provided. The methods involve administering to the subject a therapeutically effective amount of an inflammation suppressor, a therapeutically effective amount of a CD8+ T cell depleting agent, and a therapeutically effective amount of a composition comprising a lentiviral vector (LV) comprising an optimized FVIII expression cassette expressibly linked to a megakaryocyte-specific promoter. Such methods, compositions, and systems are useful to treat subjects with blood clotting disorder(s), such as hemophilia A.

Vivo gene therapy using intraosseous delivery of a lentiviralgene construct

The present disclosure provides improved compositions for the homology directed repair of the human globin locus for the prevention, treatment, or amelioration of at least one symptom of a hemoglobinopathy.

Homology directed repair compositions for the treatment of hemoglobinopathies

The present application relates to, inter alia, compositions including proteins for expression in host cells to render them resistant to rapamycin. The application further relates to methods of using the proteins, cells, and compositions disclosed therein for modulating cell signaling and for selective expansion of cells.

Rapamycin resistant cells

The present application relates to plasma cells and plasma cell precursors that express a macromolecule, such as a protein, protein mimetic or a peptide and compositions comprising these plasma cells or plasma cell precursors. The application further relates to methods of using and making the plasma cells and plasma cell precursors that express the macromolecule. Methods of treatment comprising administering the plasma cells or plasma cell precursors are also contemplated.

Engraftable cell-based immunotherapy for long-term delivery of therapeutic proteins

Aspects of the invention described herein concern the incorporation of a FOXP3 cDNA (e.g., full-length human codon-optimized cDNA) into a FOXP3 gene or a non-FOXP3 locus so as to provide constitutive or regulated FOXP3 expression in a primary human CD34cells or cells derived from edited CD34cells. In some embodiments, guide RNA sequences that are directed to FOXP3, AAVS1, or other candidate loci are used for CRISPR/Cas9-mediated gene regulation, and gene delivery cassettes for HDR based gene-modification are provided.

Expression of FOXP3 in edited CD34+ cells

Disclosed are methods of making a genetically cell that expressed FOXP3 and methods of treatment. In some embodiments, the method can providing a first nucleotide sequence, wherein the first nucleotide sequence comprises a coding strand, the coding strand comprising one or more regulatory elements and a FOXP3 gene or portion thereof providing a nuclease and performing a gene editing process on the first nucleotide sequence, which edits said one or more regulatory elements, and optionally edits the FOXP3 gene or portion thereof. Methods of treating a subject suffering from an autoimmune disease and subjects suffering the effects of organ transplantation are also provided.

Method for treating autoimmune disease using CD4 T-cells with engineered stabilization of expression of endogenous FOXP3 gene

Described herein are systems and methods for treating, inhibiting, or ameliorating X-linked disorders including Wiskott-Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) in subjects that have been identified or selected as being ones that would benefit from a therapy to treat, inhibit, or ameliorate WAS or XLT. The systems include nuclease and vector donor constructs configured for co-delivery to modify endogenous WAS locus.

Therapeutic genome editing in Wiskott-Aldrich syndrome and X-linked thrombocytopenia

The present disclosure relates to the co-expression of an endonuclease with an end-processing enzyme for the purpose of enhanced processing of the polynucleotide ends generated by endonuclease cleavage.

Coupling endonucleases with end-processing enzymes drives high efficiency gene disruption

Disclosed herein are nuclease-based systems for genome editing and methods of using the system for genome editing. Also, disclosed are approaches to enhance Cas9-mediated gene editing efficiency in primary human cells with minimal toxicity when using adeno-associated virus vectors (AAV) to express the guide RNAs necessary for CRISPR/Cas9-based genome editing in the presence of helper proteins.

Enhancing endonuclease based gene editing in primary cells

The present application generally relates to methods of genetically modifying a T-cell comprising a chimeric antigen receptor wherein the T-cell lacks a co-receptor for HIV. The application further relates to methods of making a nucleic acid encoding a chimeric antigen receptor, nucleic acids encoding a chimeric antigen receptor, and genetically modified T-cells comprising a chimeric antigen receptor disclosed herein. The application further relates to methods of treating, inhibiting, or ameliorating HIV in a subject including administering to the subject a cell disclosed herein.

CCR5 disruption of cells expressing anti-HIV chimeric antigen receptor (CAR) derived from broadly neutralizing antibodies

The present disclosure concerns methods for recombinantly producing functional ataxia-telangiectasia (ATM) protein, methods for isolating recombinant functional ATM protein, and uses of ATM protein. In particular, a method is disclosed for using a vaccinia virus vector to express ATM, and using immunoprecipitation or affinity tagging to isolate recombinant ATM.

Expression and purification of ATM protein using vaccinia virus

Novel hematopoietic-restricted tyrosine kinases are provided, where the tyrosine kinases provide for autophosphorylation and transphosphorylation. Modulation of the activity of the subject compositions can be used to restrict growth and differentiation, to correct genetic deficiencies, and to elucidate the activation pathway involved with the subject tyrosine kinases. In addition, the tyrosine kinases may be used in a variety of assays as a label or in the production of the phosphorylated peptides.

Growing community of inventors

Seattle, WA, United States of America

David J Rawlings