RICHMOND, Calif., May 9, 2016 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO), the leader in therapeutic genome editing, presented new preclinical data from the Company's proprietary In Vivo Protein Replacement Platform™ (IVPRP) program in Mucopolysaccharidosis I (MPS I) providing histologic evidence of tissue clearance of toxic glycosaminoglycans (GAGs) after a single systemic treatment. Sangamo scientists and their collaborators also presented data highlighting technological enhancements of the company's therapeutic applications, including improved AAV yields and supraphysiologic human Factor VIII (hFVIII) production in vivo, methods for highly efficient ex vivo zinc finger nuclease (ZFN)-driven targeted integration and gene knockouts at clinical scale, and treatments to enhance multipotency and long-term engraftment of ZFN-modified hematopoietic stem and progenitor cells (HSPCs).
The data were presented at the 19th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) which was held in Washington D.C. from May 4 to May 7, 2016.
"These histologic data, in a mouse model of MPS I, confirm earlier biochemical and cognitive studies and we are very excited to begin clinical evaluation of this program with a Phase 1/2 clinical study that will start in mid-2016," said Edward Lanphier, Sangamo's president and chief executive officer. "We are also pleased to report on technologic and process enhancements that the Company has made resulting in higher rates of ZFN-mediated ex vivo genome editing for both gene insertion and disruption and improved in vivo production of Factor VIII from an AAV vector, which in the past has been a notoriously difficult gene to express from a viral vector. The enhanced vector yields, combined with levels of protein expression of Factor VIII that have never been achieved before in mice or non-human primates are a testament to the engineering expertise of our research team. We look forward to updating on these studies later this year."
New histopathological analysis revealed systemic correction of cellular vacuolation in multiple tissues of MPS I mice treated with SB-318, Sangamo's ZFP Therapeutic candidate for the one-time, lasting treatment of MPS I. Cellular vacuolation, the engorgement of the lysosomes of a cell due to accumulation of GAGs, is a characteristic of the disease. Reduced levels of vacuolation were detected in various tissues of the treated MPS I mice, including the liver, spleen, lungs, kidney, heart and skeletal muscle, as well as in bone marrow, lymph nodes, bone and the spinal cord. Both the animal model study and histopathological analysis were performed as part of the Company's collaboration with the University of Minnesota.
In addition to data from the Company's IVPRP programs, Sangamo's research team presented data on recent technological advancements in process development and therapeutic applications. Specifically:
- The optimization of AAV hFVIII cDNA vector cassettes resulting in significant improvements to both vector yields and liver-specific hFVIII expression. Historically hFVIII AAV vector cassettes routinely produce viral yields that are only 20% of non-hFVIII-encoding AAV2/6 virus preparations. Sangamo reported on vector improvements that generated virus yields that were 100% of standard AAV2/6 manufacturing yields from both mammalian (HEK293) cells at the cell factory scale, as well as insect cell (baculovirus system) manufacturing at clinical scale. This result was also observed in other AAV serotypes, including AAV2/8 and AAV2/9. Administration of AAV resulted in supraphysiologic hFVIII plasma levels (overall mean 331% of normal hFVIII expression) in a mouse model of hemophilia A at 42 days post-treatment. Supraphysiologic levels of hFVIII were also achieved in non-human primates (NHPs) (peak levels up to 887% of normal hFVIII levels, overall mean 654% at highest dose tested) at doses of only 2-6x1012 vg/kg.
- Improved multipotency, the ability to differentiate into all hematopoietic lineages, and long-term engraftment of ZFN-modified HSPCs by treatment with the small-molecule epigenetic modifier, Valproic acid (VPA). Treatment with VPA also improved rates of genome editing, particularly targeted integration, in primitive HSPCs.
- Use of serum-free conditions to increase the efficiency of ZFN-mediated targeted integration in isolated T-cells.
- Generation of highly efficient (>90%) levels of biallelic knock out of single genes, the T-cell receptor (TCR) and HLA Class I protein, and > 80% of both genes simultaneously in primary T-cells. In addition, the study demonstrated simultaneous highly efficient (60-70%) targeted gene integration into these sites. These methods have potential use in the development of allogeneic T-cell therapies.
Finally, Sangamo scientists and members of the Company's senior management team were invited speakers at several scientific symposia at the meeting. Thomas Wechsler, Ph.D., project leader of the Company's lysosomal storage disease (LSD) programs, was one of three speakers invited to present in the ASGCT Scientific Symposium, "Targeting the Liver with Gene and Cell Therapeutics." Michael Holmes, Ph.D., Sangamo's vice president of research, presented an overview of Sangamo's programs in the "Special Symposium on Concepts and Clinical Applications of Genome Editing." In addition, Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer, was one of four speakers in the Scientific Symposium, "Navigating the New RAC Review for Gene Therapy." In his presentation, Dr. Ando discussed the new NIH Recombinant DNA Advisory Committee (RAC) review guidelines and their impact on the regulatory process for gene therapies.
About Sangamo's IVPRP for LSDs
Sangamo's MPS I program (SB-318) is the first LSD program, based on the Company's proprietary IVPRP approach. The U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application for this program and Sangamo expects to initiate a Phase 1/2 clinical study in mid-2016. The IVPRP uses Sangamo's ZFN genome editing technology to precisely target and insert a therapeutic gene of interest into the Albumin locus in the genome of liver cells. The goal is to produce stable, therapeutic levels of the corrective protein that is deficient in a disease by harnessing the powerful albumin promoter in liver cells.
In early March 2016, at the WorldSymposium™ Sangamo scientists and collaborators presented data for both of its MPS I and MPS II programs. The data demonstrate stable production of active human IDUA (hIDUA) and human IDS (hIDS) enzymes for MPS I and MPS II, respectively, from the liver of treated animals, which were then secreted into the blood plasma and taken up by various secondary tissue through the end of the 120 day study. Significant increases of hIDUA and hIDS enzyme activity were observed in secondary tissues, including the brain, as well as statistically significant reduction of GAG biomarker levels. Furthermore, treated animals demonstrated preservation of cognitive function when assessed using the Barnes Maze, which evaluates memory and spatial learning capabilities of animals, providing further evidence of the ability of the therapeutic enzymes to cross the blood brain barrier.
Sangamo BioSciences, Inc. is focused on Engineering Genetic Cures® for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic genome editing and gene regulation. The Company's proprietary In Vivo Protein Replacement Platform™ (IVPRP) approach is focused on monogenic diseases, including hemophilia and lysosomal storage disorders. Based on its proprietary IVPRP approach, Sangamo is initiating Phase 1/2 clinical trials for hemophilia B, the first in vivo genome editing application cleared by the FDA, and MPS I. In addition, Sangamo has a Phase 2 clinical program to evaluate the safety and efficacy of novel ZFP Therapeutics® for the treatment of HIV/AIDS (SB-728). The Company has also formed a strategic collaboration with Biogen Inc. for hemoglobinopathies, such as sickle cell disease and beta-thalassemia, and with Shire International GmbH to develop therapeutics for Huntington's disease. It 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, references relating to research and development of novel ZFNs and therapeutic applications of Sangamo's ZFP technology platform for the treatment of MPS I,MPS II and hemophilia A, the efficient modification, differentiation and engraftment of HSPCs and genome modification of T-cells, and the timing of initiation of clinical trials and data presentation. 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 safety, 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 public filings with the Securities and Exchange Commission, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.
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