RICHMOND, Calif., Dec. 10, 2013 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced the presentation of new pre-clinical data demonstrating therapeutic levels of gene modification in non-human primates (NHPs) from its In Vivo Protein Replacement Platform. Based on Sangamo's zinc finger DNA-binding protein (ZFP) genome-editing technology, the platform enables the permanent production of therapeutic proteins from a specific genomic site in the liver with a single systemic treatment, potentially providing curative treatments for a range of monogenic diseases such as hemophilia and lysosomal storage disorders (LSD) including Gaucher and Fabry disease. Such diseases are currently treated by regular infusions of protein or enzyme replacement therapy (ERT) throughout the patient's life. The data were presented at the 55th Annual Meeting of the American Society of Hematology (ASH) which is being held in New Orleans.
"These data provide proof of concept for this broadly applicable genome editing strategy by demonstrating that our process is scalable to large animals and by validating the use of the albumin safe harbor as a site for expression of therapeutic proteins," said Philip Gregory. D. Phil., Sangamo's vice president of research and chief scientific officer. "We have further optimized Sangamo's ZFN system and demonstrated that a single systemic treatment enables stable liver-specific production of replacement protein. Early data in primates suggest that we can achieve circulating levels of protein above the threshold for therapeutic effect, which we believe are sufficient for the correction of a range of monogenic diseases. Our data demonstrate expression of replacement enzymes for multiple different proteins, including those deficient in lysosomal storage disorders, which serves to demonstrate the potential of this approach for a broad range of other monogenic diseases."
Sangamo's In Vivo Protein Replacement Platform makes use of a highly expressed and liver specific genomic "safe-harbor site" that can be edited with ZFP nucleases (ZFNs) to accept and express any therapeutic gene and thus permanently produce high levels of the missing protein with a single treatment. The gene encoding albumin, the most abundant protein in blood serum, was chosen as a safe harbor site because it is active exclusively in the liver. The albumin promoter is highly active, continuously producing large amounts of albumin protein (approximately 15g/day) which is in excess of the body's requirements. With such a large capacity for protein production, targeting and co-opting a very small percentage of the albumin gene's production capacity is sufficient to safely produce the needed replacement protein at therapeutically relevant levels with no significant effect on albumin production. The study was performed as part of Sangamo's collaboration with Shire and in the laboratory of Katherine A. High, M.D., director of the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. Dr. High is a Howard Hughes Medical Institute Investigator, and Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.
"These data represent an important milestone in the progress of our monogenic disease programs towards the clinic," stated Edward Lanphier, Sangamo's president and chief executive officer. "Our In Vivo Protein Replacement Platform is a highly leverageable and disruptive application of our ZFN-mediated genome editing technology and can potentially be applied to any disease-relevant gene where enabling the liver to provide a stable source of corrective replacement protein will be therapeutic. The NHP data presented at ASH represent a significant de-risking step and provide important proof of concept and validation for this entire strategy."
The data were presented in an oral presentation:
Abst. #720 ZFN Mediated Targeting of Albumin "Safe Harbor" Results in Therapeutic Levels of Human Factor VIII in a Mouse Model of Hemophilia A
Monday, December 9, 2013: 5:45 PM
Scientists demonstrated efficient ZFN-mediated gene addition into the albumin locus in adult mouse models of hemophilia A and B with a single systemic administration of ZFNs and a donor DNA sequence encoding a corrective human Factor VIII or IX gene, respectively. This permanent correction resulted in the production of robust, stable levels of circulating active Factor VIII and Factor IX protein that normalize clotting times in hemophilic mice.
Data were presented demonstrating the broad utility of this method for the potential treatment of a wide range of monogenic diseases. In these additional studies, the albumin-specific ZFN strategy was used in combination with appropriately designed donor DNA sequences encoding a diverse range of protein factors including alpha-galactosidase which is deficient in Fabry disease, beta-glucosidase (Gaucher disease), Iduronate-2 Sulfatase (Hunter disease) and alpha-L-Iduronidase (Hurler disease).
The feasibility and scalability of the approach was also evaluated in NHPs (Rhesus monkeys), an important large animal model that has been previously used in the development of novel gene-based therapies for monogenic diseases such as hemophilia. These NHP data revealed specific ZFN-mediated modification of the albumin locus by deep-sequencing analysis of liver biopsy samples from treated animals. There were no significant alterations in circulating albumin levels. Analysis of T-cells isolated from both spleen and lymph node, demonstrated that the animals did not mount an immune response to either the ZFNs or the vector used for delivery. Importantly, ZFN-mediated modification of the albumin locus in NHPs resulted in levels of modification which are sufficient to provide a therapeutic effect. In a program update, early experiments demonstrate expression of the encoded therapeutic protein at levels that were up to three-fold the amount required for therapeutic effect.
Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase 1/2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. As part of its acquisition of Ceregene, Inc., Sangamo acquired a fully-enrolled and funded, double-blind, placebo-controlled Phase 2 trial to evaluate NGF-AAV (CERE-110) in Alzheimer's disease. Sangamo's other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington's disease and hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire AG to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases and has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company's website at www.sangamo.com.
ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, the potential of ZFNs to treat a broad range of human monogenic diseases, including hemophilia and LSDs, research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.
SOURCE Sangamo BioSciences, Inc.