Nature publishes Sangamo's gene correction strategy for A1AT deficiency

Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced the publication of a preclinical study demonstrating highly specific, functional correction of the alpha 1-antitrypsin (A1AT) gene defect in patient-derived induced pluripotent stem cells (iPSCs) using zinc finger nucleases (ZFNs).  The study, published in Nature, further highlights the precision and broad applicability of ZFN-based genome-editing for the development of ZFP Therapeutics® for the treatment of monogenic diseases.  

"These data demonstrate the potential of combining human iPSCs with ZFN-driven gene correction to generate differentiated cell-based therapies," stated Philip Gregory, D. Phil., Sangamo's vice president of research and chief scientific officer.  "Importantly, analysis of the entire coding sequence of a ZFN-corrected iPSC line revealed that the only modification attributable to ZFN activity was the intended repair of the A1AT gene. This demonstrates the singular specificity that can be achieved using Sangamo's ZFP technology."

The work was carried out in collaboration with scientists at the Wellcome Trust Sanger Institute, the University of Cambridge, U.K., DNAVEC Corporation of Japan, and several laboratories in Europe. The study was published as an Advance Online Publication in Nature on October 12, 2011 (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10424.html).

"Our precise ZFN genome-editing technology enables Sangamo to modify any target gene of interest," said Edward Lanphier, Sangamo's president and chief executive officer. "As this study demonstrates, our platform can generate novel ZFP Therapeutic options for diseases that have a well-defined genetic cause.  In addition to our ZFN clinical programs in HIV, addressing unmet medical needs such as hemophilia and other monogenic diseases is a focus of our therapeutic pipeline."

The paper entitled, "Targeted Gene Correction of Alpha 1-Antitrypsin Deficiency in Induced Pluripotent Stem Cells" describes highly specific and efficient ZFN-mediated correction of a defective human A1AT gene in iPSCs derived from skin cells from individuals with alpha 1-antitrypsin deficiency (A1ATD). The A1AT gene encodes a protein that is made in the liver and protects the lungs and liver from damage.  A1ATD is the most common inherited metabolic disease of the liver, and is the result of a single mutation in the A1AT gene.  iPSCs can be reprogrammed to develop into a wide range of tissues.  Reintroduction of gene-corrected iPSCs into patients with an identified gene defect may provide a treatment approach to genetic disease.

iPSCs that had undergone ZFN-mediated correction were differentiated in vitro into hepatocyte-like cells (the main cell type affected in the disease) that secreted active A1AT protein at levels comparable to normal adult hepatocytes.  Transplanted ZFN-corrected iPSCs were found to "colonize" livers of a mouse model system. Sequence analysis of the coding genome of a ZFN-corrected hiPSC line revealed that the sole change in the genome attributable to ZFN activity was the repair of the A1AT gene, demonstrating the precision of the modification.