The Children's Hospital of Philadelphia

Memorial Sloan Kettering Cancer Center

Cornell University

Sloan-kettering Institute for Cancer Research

Stefano Rivella

Michel Sadelain

Joseph R Bertino

Chad May

Gerd Blobel

Wulan Deng

Laura Breda

Alisa Dong

Carla Casu

Maxwell Chappell

The present invention provides methods, agents, compounds, and compositions useful for administering to subjects having or at risk of having anemias. In certain embodiments, methods herein comprise administering two agents to a subject, which are useful for the treatment of an anemia.

Methods of improving anemias by combining agents

Methods and compositions for producing hemoglobin and treating alpha-thalassemia are disclosed.

Compositions and methods for hemoglobin production

Provided are compositions and methods for inducing expression of human beta-globin in erythrocytes for use in prophylaxis and/or therapy of a hemoglobinopathy in an individual. The method generally entails introducing into CD34+ cells a poly-nucleotide encoding: i) a 5' long terminal repeat (LTR) and a self-inactivating 3&#x2032; LTR; ii) at least one polyadenylation signal; iii) at least one promoter; iv) a globin gene locus control region (LCR); v) an ankyrin insulator element (Ank); vi) a Woodchuck Post-Regulatory Element (WPRE) configured such that the WPRE does not integrate into a target genome; and vii) a sequence that is a reverse complement of a sequence encoding human beta-globin, and can include beta-globin that has a PT87Q mutation. Intron 2 of the beta globin gene can be a complete intron. Modified erythrocyte progenitor cells, recombinant vectors and virions comprising recombinant polynucleotides, and methods of making the vectors and virions are included.

Viral vectors for prophylaxis and therapy of hemoglobinopathies

Recombinant lentiviral vectors having a region encoding a functional &#x3b2;-globin gene; and large portions of the &#x3b2;-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of &#x3b2;-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including &#x3b2;-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than untransformed cells allows selection by treatment of the cells with the corresponding drug.

Vector encoding human globin gene and use thereof in treatment of hemoglobinopathies

Recombinant lentiviral vectors having a region encoding a functional &#x3b2;-globin gene; and large portions of the &#x3b2;-globin locus control regions which include DNase I hypersensitive sites HS2, HS3 and HS4 provides expression of &#x3b2;-globin when introduced into a mammal, for example a human, in vivo. Optionally, the vector further includes a region encoding a dihydrofolate reductase. The vector may be used in treatment of hemoglobinopathies, including &#x3b2;-thalessemia and sickle-cell disease. For example, hematopoietic progenitor or stem cells may be transformed ex vivo and then restored to the patient. Selection processes may be used to increase the percentage of transformed cells in the returned population. For example, a selection marker which makes transformed cells more drug resistant than un-transformed cells allows selection by treatment of the cells with the corresponding drug.

Growing community of inventors

New York, NY, United States of America

Stefano Rivella