More good news for gene therapy: Sangamo Biosciences

Good to see many therapeutic options coming through the pipeline. Stay positive. Chelate. Many options will be available in the future and different options may work for different patients.  Note: they are hoping to begin trials in 2016.  

SANGAMO BIOSCIENCES ANNOUNCES JOINT STEERING COMMITTEE DECISION TO CONSOLIDATE ZFP THERAPEUTIC® STRATEGY FOR HEMOGLOBINOPATHIES
Development Decision Leverages Recent Data with New ZFN-mediated Genome Editing Approach for Both Sickle Cell Disease and Beta-Thalassemia Programs
Richmond, Calif., May 13, 2015 – Sangamo BioSciences, Inc. (NASDAQ: SGMO) announced that it will consolidate development paths for the zinc finger nuclease (ZFN)-mediated genome editing programs targeting beta-thalassemia and sickle cell disease (SCD). This decision was based on preclinical data that support the development of the “BCL11A Enhancer” target for these clinical programs, indicating that it has the potential to provide the most efficient path to clinical proof of concept and subsequent development. While the beta-thalassemia program was initiated with a BCL11a knockout strategy, the SCD program already employs the BCL11A Enhancer approach. The decision to consolidate the strategy for these two programs was made by the joint steering committee (JSC) governing the programs, including Sangamo’s collaborator Biogen.
“Biogen’s experience in the development of novel therapeutics has been critical as we work to advance these ZFP Therapeutics into the clinic,” said Edward Lanphier, Sangamo’s president and chief executive officer. “While our joint decision will result in a delay in the initiation of the beta-thalassemia Phase 1 clinical trial, we believe that the efficiency of the consolidated development path and potential benefit to patients clearly support this decision.”
Mr. Lanphier added, “We are committed to rapidly moving this exciting new therapeutic approach powered by our ZFN genome editing technology into human clinical trials. The alignment of the beta-thalassemia and SCD programs to use the same specific ZFN reagent will enable more rapid and efficient co-development and provide both beta-thalassemia and sickle cell disease patients with a potentially safe and efficacious single-administration treatment with a life-long therapeutic effect.”
“The quality of the clinical candidate and a focus on patient benefit drives our development decisions,” said Olivier Danos, Ph.D., Biogen’s senior vice president of gene therapy. “Sangamo's ability to rapidly move from identification of a new DNA target to a highly specific genome editing therapeutic lead candidate has enabled us to quickly deploy the latest scientific knowledge against both of these important genetic diseases.”
Sangamo intends to file a new Investigational New Drug (IND) application for the “BCL11A Enhancer” approach for beta-thalassemia and anticipates initiating a Phase 1 clinical trial in 2016.
About the BCL11A Enhancer and BCL11A Knockout approaches
Both beta-thalassemia and SCD manifest several months after birth, when patients’ cells switch from producing functional fetal globin to a mutant form of adult beta-globin, which causes their condition. Naturally occurring increased levels of fetal hemoglobin have been shown to reduce the severity of both SCD and beta-thalassemia disorders in adulthood. The collaborative development program uses ZFN-mediated genome editing of a patient’s own hematopoietic stem and progenitor cells (HSPCs) to increase production of fetal globin in cells that will ultimately become red blood cells (RBCs). This novel approach uses the targeted specificity of ZFNs which need to be expressed in the cell only transiently to have a permanent effect.

Building upon recent data on the regulation of fetal hemoglobin, Sangamo and Biogen have developed two related but distinct ZFN-mediated genome editing approaches to disrupt critical aspects of the regulatory pathway that, in early infancy, leads to the switch in production from fetal to adult globin.
Initially, Biogen and Sangamo developed a strategy for beta-thalassemia that specifically knocked out the gene encoding the BCL11A transcription factor, a critical regulator of the switch from fetal to adult globin production. A second approach was initiated for the SCD program, which involved the disruption of the more recently described erythroid-specific “Enhancer” of BCL11A expression, a regulatory DNA sequence in the genome that is essential for expression of BCL11A but that is functional exclusively in cells destined to become RBCs. Both ZFN-mediated approaches were found to be equally specific and efficient leading to similar increases in fetal globin production. However, the Enhancer approach was found to have certain advantages, including its specificity for RBC producing cells, making it a preferable therapeutic strategy for hemoglobinopathies. Thus, the determination was made that the beta-thalassemia program should follow BCL11A Enhancer approach, like the SCD program.
“Sangamo’s design and selection process enables rapid optimization of highly specific lead ZFN therapeutics,” commented Philip Gregory, D.Phil., Sangamo’s senior vice president of research and chief scientific officer. “While the discovery of the BCL11A Enhancer as a potential target was made relatively recently, the team generated critical data that supported the Enhancer approach in time for this strategy to be used for both the beta-thalassemia and the sickle cell disease programs.”
Preclinical data supporting the Enhancer program will be presented at 4:15 pm ET, today, Wednesday, May 13, 2015 at the 18th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). Abstract #53 “From GWAS to the Clinic: Genome-Editing the Human Bcl11a Erythroid Enhancer for Fetal Globin Elevation in the Hemoglobinopathies.”
About Sangamo’s ZFN Therapeutic Approach to Hemoglobinopathies
Sangamo’s proprietary ZFN genome editing technology enables multiple approaches to the correction of SCD and beta-thalassemia. Both diseases manifest after birth, when patients switch from producing functional fetal gamma-globin to a mutant form of adult beta-globin, which causes their condition. Naturally occurring increased levels of therapeutic fetal hemoglobin have been shown to reduce the severity of both SCD and beta-thalassemia disorders in adulthood. In hematopoietic stem cells (HSCs), Sangamo’s genome editing can be used to specifically disrupt the genes encoding key transcriptional regulators, such as BCL11A, to reverse the switch from expression of the mutant adult beta-globin back to the production of functional fetal gamma-globin. Alternatively, the technology can be used to precisely disrupt a key DNA sequence that acts as a powerful tissue and developmental stage “Enhancer” of BCL11A expression.
A bone marrow transplant (BMT) of HSCs from a “matched” related donor (allogeneic BMT) is curative for both diseases. However, this therapy is limited due to the scarcity of matched donors and the significant risk of Graft versus Host Disease (GvHD) after transplantation of the foreign cells. By performing genome editing in HSPCs that are isolated from and subsequently returned to the same patient, an autologous HSPC transplant, Sangamo's approach eliminates both the need for a matched donor and the risk of acute and chronic GvHD. The ultimate goal of this approach is to develop a one-time curative treatment for SCD and beta-thalassemia.
About Hemoglobinopathies
Mutations in the genes encoding beta-globin, a subunit of the oxygen-carrying protein of red blood cells, lead to the hemoglobinopathies SCD and beta-thalassemia. The mutation in beta-globin that gives rise to SCD causes the red blood cells to form an abnormal sickle or crescent shape making them adherent, fragile and less able to deliver oxygen to tissues, and they can become lodged in small blood vessels and interrupt healthy blood flow. These problems further decrease the amount of oxygen flowing to body tissues. Almost all patients with SCD have painful episodes (called crises), which can last from hours to days, and have progressive organ damage, resulting in shortened lifespan. Current standard of care is to manage and control symptoms and to limit the number of crises. Current treatments, including blood transfusions, iron-chelation therapy and administration of hydroxyurea, pain medications and antibiotics, do not address the underlying cause of disease, and life expectancy remains substantially reduced in patients with SCD. The CDC estimates that there are currently 90,000 to 100,000 Americans living with SCD which occurs in approximately 1 out of every 500 African-American births and 1 out of every 36,000 Hispanic-American births.
There are several forms of beta-thalassemia caused by mutations in the beta-globin gene. Generally, the disorder results in excessive destruction of red blood cells leading to life-threatening anemia, enlarged spleen, liver and heart, and bone abnormalities. Beta-thalassemia major is a severe form of thalassemia that requires regular, often monthly, blood transfusions and subsequent iron-chelation therapy to treat iron overload. The CDC estimates that 1,000 people have beta-thalassemia major in the United States, and an unknown number carry the genetic trait and can pass it on to their children. Thalassemia is most common among people of Mediterranean descent and is also found among people from the Arabian Peninsula, Iran, Africa, Southeast Asia and Southern China.
About Sangamo
Sangamo BioSciences, Inc. is focused on Engineering Genetic CuresTM for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic gene regulation and genome editing. The Company has a Phase 2 clinical program to evaluate the safety and efficacy of novel ZFP Therapeutics® for the treatment of HIV/AIDS (SB-728). Sangamo's other therapeutic programs are focused on monogenic and rare diseases. The Company has formed a strategic collaboration with Shire International GmbH to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases, and with Biogen Inc. for hemoglobinopathies, such as sickle cell disease and beta-thalassemia. It has also 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 to the research and development of novel ZFNs, the timing of filing of Investigational New Drug (IND) applications and the initiation of clinical trials and the potential therapeutic applications of the ZFN technology for the treatment of hemoglobinopathies, SCD and beta-thalassemia, and the efficiency and benefits resulting from the consolidation of SCD and beta-thalassemia programs using the BCL11A Enhancer approach. Actual results may differ materially from these forward-looking statements due to a number of factors, including technological challenges, uncertainties and risks relating to clinical trials, compliance with regulatory and other requirements, the ability of Sangamo to develop commercially viable products and technological developments by our competitors. See the SEC filings, and in particular, the risk factors described in Sangamo’s Annual Reports on Form 10-K and most recent Quarterly Reports on Form 10-Q. Sangamo does not assume any obligation to update the forward-looking information contained in this press release.