Sangamo Publishes Preclinical Data Showing Gene Correction in SCID-X1 Human Hematopoietic Stem Cells

Sangamo BioSciences, Inc.

announced today the publication in Nature of data demonstrating efficient zinc finger nuclease (ZFN)-mediated, targeted gene insertion that resulted in correction of the genetic defect in stem cells from an individual with X-linked severe combined immunodeficiency (SCID-X1). Importantly, the study demonstrates that the treatment successfully targets a class of hematopoietic stem cells (HSCs) that are responsible for the long term repopulation of the bone marrow following transplant. The data support the clinical translation of this approach for SCID-X1, other immunodeficiencies and monogenic diseases. "The ability to accomplish targeted integration of a therapeutic gene into HSCs represents a major step forward in the quest for more precise and safe gene therapies," stated Luigi Naldini, M.D., Ph.D., Director, San Raffaele Telethon Institute for Gene Therapy (TIGET) and a senior author on the paper. "We used ZFNs to promote insertion of a corrective DNA sequence into the IL2RG gene in HSCs derived from either cord blood or bone marrow. This strategy enables correction of the inherited functional defect of the gene while at the same time restoring its expression under physiological control. This work should open a path to the development of safer and potentially curative treatments for SCID-X1 and, conceivably, other genetic disorders." The study, entitled "Targeted genome editing in human repopulating haematopoietic stem cells," was conducted at TIGET by a team of scientists led by Dr. Naldini in collaboration with Sangamo scientists, and was published as an Advance Online Publication in Nature http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13420.html. Researchers capitalized on the fact that ZFN-mediated genome editing requires only a transient expression of the ZFNs to effect a permanent change in the genome.  They used messenger RNA and electroporation to deliver the ZFNs and a non-integrating vector, an Integrase Defective Lentiviral Vector (IDLV), to provide a corrective therapeutic DNA sequence, a so-called "donor template," to human stem cells. This delivery approach, in combination with modified culture conditions for the cells, increased the efficiency of gene transfer and targeted integration particularly in more primitive longer-lasting stem cells, to levels that can be used therapeutically to potentially treat a range of monogenic diseases. The study, which included testing the proposed gene correction strategy in vitro in HSCs derived from the bone marrow of a symptomatic four-month-old SCID-X1 patient, demonstrated the functional reconstitution of the IL2RG gene in the lymphoid progeny of corrected HSCs in vivo. "Sangamo's ZFN gene-editing platform provides precise permanent targeted integration of therapeutic genes in contrast to conventional integrating vector approaches which insert genes randomly," stated Philip Gregory, D. Phil., Sangamo's senior vice president, research and chief scientific officer, and a co-author of the study. "This work demonstrates efficient targeted gene insertion in long-term repopulating HSCs which support multilineage differentiation in to all cells of the blood. These data support the application of ZFN-mediated gene modification across a range of monogenic diseases."