Novel Genome-Editing Approach Offers a Potential Cure for Both Diseases
RICHMOND, CA, USA I December 9, 2013 I Sangamo BioSciences, Inc. (SGMO) announced the presentation of preclinical data from its ZFP Therapeutic program for the treatment and potential cure of both sickle cell disease (SCD) and beta-thalassemia. The data demonstrate that Sangamo’s approach, using its proprietary and highly specific zinc finger nuclease (ZFN) gene-editing technology, enables permanent increase in the expression of fetal gamma-globin in adult red blood cells (RBCs). This increase restores the normal balance of globin proteins that together form the oxygen-carrying hemoglobin of RBCs. In addition, the pre-clinical studies demonstrate that this can be accomplished at clinical-scale reproducibly achieving high levels (up to 80 percent) of gene editing in hematopoietic stem cells (HSCs).
The study was carried out in collaboration with scientists in the laboratory of George Stamatoyannopoulos, M.D., Dr.Sci., Professor of Medicine and Genome Sciences at the University of Washington. The data were presented at the 55th Annual Meeting of the American Society of Hematology (ASH), which is being held in New Orleans.
“These preclinical data demonstrate that Sangamo’s precise ZFN genome editing technology enables a unique approach that can be used to treat, and potentially cure, both sickle cell disease and beta-thalassemia,” said Mark Walters, M.D., Director of Blood and Marrow Transplantation at Children’s Hospital & Research Center Oakland, and a leader of one of the clinical teams that will be conducting the first Phase 1 clinical trial of this ZFP Therapeutic in transfusion-dependent beta thalassemia patients. “The modification process is extremely efficient and scalable. We look forward to conducting a clinical study that employs Sangamo’s technology in a patient’s own stem cells to potentially provide a safer approach than current therapies, and eliminate the need for life-long medications and red blood cell transfusions that are currently the standard of care for these disorders.”
SCD and beta-thalassemia are genetic diseases of the blood caused by mutations in the beta-globin gene. In SCD, the gene defect in beta-globin results in an abnormal hemoglobin which causes the RBCs to develop a sickle, or crescent, shape. These abnormal RBCs are stiff and sticky and can block blood flow in the small blood vessels of the limbs and organs resulting in pain, organ damage and an increased risk of infection. The gene defect responsible for beta-thalassemia leads to impaired production of hemoglobin, the iron-containing protein in red blood cells (RBCs) that carry oxygen from the lungs to the tissues, and results in a failure to make healthy RBCs. Individuals with thalassemia are therefore dependent on blood transfusions for survival.
During development, a fetal form of hemoglobin is made using a beta-like globin called gamma- or fetal-globin. In infancy, this fetal form of hemoglobin fully protects beta-thalassemia and SCD patients from developing disease symptoms. Later in childhood however, production of fetal hemoglobin ceases and is replaced by synthesis of adult-type beta-globin chains that are defective in beta-thalassemia and SCD patients and symptoms of disease appear. It is well-known that the persistence of fetal hemoglobin beyond the newborn stage lessens the severity of both of these hemoglobin disorders in the adult. The goal of Sangamo’s therapy is to enable production of normal RBCs in SCD and to eliminate, or greatly reduce, the need for chronic blood transfusions in beta-thalassemia.
Sangamo has used its proprietary ZFN genome-editing technology to precisely knock out key regulators of the transcriptional switch from fetal to adult beta-globin expression, such as BCL11A, enabling the permanent production of therapeutic fetal hemoglobin. The increased fetal gamma globin restores the normal balance of the alpha- and beta-like globin proteins that together form the oxygen-carrying hemoglobin of RBCs and the production of normal levels of hemoglobin and RBCs. Comparable efficacy is observed in cells from healthy volunteers and cells from SCD and beta-thalassemia patients.
Importantly, by performing this genome editing in HSCs that are isolated and returned to the same patient, a so-called autologous bone marrow transplant (BMT), Sangamo’s approach eliminates both the need for a matched donor and the risk of acute and chronic graft-versus-host disease (GvHD). The unmet medical need in transfusion-dependent beta-thalassemia is significant, with reduced life expectancy due to multi-organ failure caused by iron overload, blood-borne infections and other disease complications. A 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 GvHD after transplantation of the foreign cells.
In May 2013, Sangamo was awarded a $6.4 million Strategic Partnership Award from the California Institute for Regenerative Medicine (CIRM) to develop this potentially curative ZFP Therapeutic for beta-thalassemia. The four-year grant provides matching funds for preclinical work that will support an Investigational New Drug (IND) application and a Phase 1 clinical trial in transfusion-dependent beta-thalassemia patients, which will be carried out at City of Hope by a team directed by Dr. Stephen Forman, M.D., F.A.C.P., Director, Department of Hematology and Hematopoietic Cell Transplantation and at Children’s Hospital & Research Center Oakland.
“These data demonstrate the versatility, specificity and high level of efficiency of Sangamo’s ZFP genome-editing technology,” said Edward Lanphier, Sangamo’s president and CEO. “Although our initial clinical study is planned for beta-thalassemia, this same ZFP Therapeutic approach can be directly applied to related hemoglobinopathies such as sickle cell disease. We look forward to working with a team of world-renowned experts in this field, including the team at Children’s Hospital & Research Center Oakland, City of Hope and our colleagues at CIRM, to bring this treatment through IND application and into Phase 1 clinical testing.”
The abstract for this oral presentation (#434 -“Targeted Gene Modification In Hematopoietic Stem Cells: A Potential Treatment For Thalassemia and Sickle Cell Anemia”), along with a second Sangamo abstract (#433 – “Using Forced Chromatin Looping to Overcome Developmental Silencing of Embryonic and Fetal beta-Type Globin Genes In Adult Erythroid Cells”), were two of three studies highlighted at a press briefing organized by the American Society for Hematology.
Sangamo Abstracts at ASH Pertinent to Sangamo’s Programs in Hemoglobinopathies
Abstract#433– Using Forced Chromatin Looping to Overcome Developmental Silencing of Embryonic and Fetal Beta-Type Globin Genes in Adult Erythroid Cells
Oral Session 112: Thalassemia and Globin Gene Regulation: Targeted Engineering of Globin Gene Expression
Monday, December 9, 2013: 2:45 PM
Abstract#434– Targeted Gene Modification in Hematopoietic Stem Cells: A Potential Treatment For Thalassemia and Sickle Cell Anemia
Oral Session 112: Thalassemia and Globin Gene Regulation: Targeted Engineering of Globin Gene Expression
Monday, December 9, 2013: 3:00 PM
Abstract#2904 –Zinc Finger Nucleases Targeting the Beta-Globin Locus Drive Efficient Correction of the Sickle Mutation in CD34+ Cells
Session 801: Gene Therapy and Transfer: Poster II
Sunday, December 8, 2013, 6:30 PM-8:30 PM
Abstract#4213– Autologous Hematopoietic Stem/Progenitor Cell (HSPC) Therapy for Monogenic Blood Disorders: Scalable, cGMP-Compliant Process for Generating Highly Efficient Genome Edited HSPC
Session 801: Gene Therapy and Transfer: Poster III
Monday, December 9, 2013, 6:00 PM-8:00 PM
About SCD and Beta-Thalassemia
Mutations in the genes encoding globin, the oxygen carrying protein of red blood cells, lead to the hemoglobinopathies, sickle cell disease (SCD) and beta-thalassemia. The mutation giving rise to SCD causes the red blood cells to form an abnormal sickle or crescent shape, making them fragile and less able to deliver oxygen to tissues. They can also get stuck more easily in small blood vessels and break into pieces that can 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. Current standard of care is to manage and control symptoms, and to limit the number of crises. Treatments include blood transfusions, iron chelation therapy and administration of hydroxyurea, pain medications and antibiotics. The CDC currently estimates that there are 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, but generally the disorder results in excessive destruction of red blood cells leading to life-threatening anemia, enlarged spleen, liver and heart, and bone abnormalities. Cooley’s anemia (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 currently estimates that 1,000 people have Cooley’s anemia 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 research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase1/2 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.
SOURCE: Sangamo Biosciences
Post Views: 173
Novel Genome-Editing Approach Offers a Potential Cure for Both Diseases
RICHMOND, CA, USA I December 9, 2013 I Sangamo BioSciences, Inc. (SGMO) announced the presentation of preclinical data from its ZFP Therapeutic program for the treatment and potential cure of both sickle cell disease (SCD) and beta-thalassemia. The data demonstrate that Sangamo’s approach, using its proprietary and highly specific zinc finger nuclease (ZFN) gene-editing technology, enables permanent increase in the expression of fetal gamma-globin in adult red blood cells (RBCs). This increase restores the normal balance of globin proteins that together form the oxygen-carrying hemoglobin of RBCs. In addition, the pre-clinical studies demonstrate that this can be accomplished at clinical-scale reproducibly achieving high levels (up to 80 percent) of gene editing in hematopoietic stem cells (HSCs).
The study was carried out in collaboration with scientists in the laboratory of George Stamatoyannopoulos, M.D., Dr.Sci., Professor of Medicine and Genome Sciences at the University of Washington. The data were presented at the 55th Annual Meeting of the American Society of Hematology (ASH), which is being held in New Orleans.
“These preclinical data demonstrate that Sangamo’s precise ZFN genome editing technology enables a unique approach that can be used to treat, and potentially cure, both sickle cell disease and beta-thalassemia,” said Mark Walters, M.D., Director of Blood and Marrow Transplantation at Children’s Hospital & Research Center Oakland, and a leader of one of the clinical teams that will be conducting the first Phase 1 clinical trial of this ZFP Therapeutic in transfusion-dependent beta thalassemia patients. “The modification process is extremely efficient and scalable. We look forward to conducting a clinical study that employs Sangamo’s technology in a patient’s own stem cells to potentially provide a safer approach than current therapies, and eliminate the need for life-long medications and red blood cell transfusions that are currently the standard of care for these disorders.”
SCD and beta-thalassemia are genetic diseases of the blood caused by mutations in the beta-globin gene. In SCD, the gene defect in beta-globin results in an abnormal hemoglobin which causes the RBCs to develop a sickle, or crescent, shape. These abnormal RBCs are stiff and sticky and can block blood flow in the small blood vessels of the limbs and organs resulting in pain, organ damage and an increased risk of infection. The gene defect responsible for beta-thalassemia leads to impaired production of hemoglobin, the iron-containing protein in red blood cells (RBCs) that carry oxygen from the lungs to the tissues, and results in a failure to make healthy RBCs. Individuals with thalassemia are therefore dependent on blood transfusions for survival.
During development, a fetal form of hemoglobin is made using a beta-like globin called gamma- or fetal-globin. In infancy, this fetal form of hemoglobin fully protects beta-thalassemia and SCD patients from developing disease symptoms. Later in childhood however, production of fetal hemoglobin ceases and is replaced by synthesis of adult-type beta-globin chains that are defective in beta-thalassemia and SCD patients and symptoms of disease appear. It is well-known that the persistence of fetal hemoglobin beyond the newborn stage lessens the severity of both of these hemoglobin disorders in the adult. The goal of Sangamo’s therapy is to enable production of normal RBCs in SCD and to eliminate, or greatly reduce, the need for chronic blood transfusions in beta-thalassemia.
Sangamo has used its proprietary ZFN genome-editing technology to precisely knock out key regulators of the transcriptional switch from fetal to adult beta-globin expression, such as BCL11A, enabling the permanent production of therapeutic fetal hemoglobin. The increased fetal gamma globin restores the normal balance of the alpha- and beta-like globin proteins that together form the oxygen-carrying hemoglobin of RBCs and the production of normal levels of hemoglobin and RBCs. Comparable efficacy is observed in cells from healthy volunteers and cells from SCD and beta-thalassemia patients.
Importantly, by performing this genome editing in HSCs that are isolated and returned to the same patient, a so-called autologous bone marrow transplant (BMT), Sangamo’s approach eliminates both the need for a matched donor and the risk of acute and chronic graft-versus-host disease (GvHD). The unmet medical need in transfusion-dependent beta-thalassemia is significant, with reduced life expectancy due to multi-organ failure caused by iron overload, blood-borne infections and other disease complications. A 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 GvHD after transplantation of the foreign cells.
In May 2013, Sangamo was awarded a $6.4 million Strategic Partnership Award from the California Institute for Regenerative Medicine (CIRM) to develop this potentially curative ZFP Therapeutic for beta-thalassemia. The four-year grant provides matching funds for preclinical work that will support an Investigational New Drug (IND) application and a Phase 1 clinical trial in transfusion-dependent beta-thalassemia patients, which will be carried out at City of Hope by a team directed by Dr. Stephen Forman, M.D., F.A.C.P., Director, Department of Hematology and Hematopoietic Cell Transplantation and at Children’s Hospital & Research Center Oakland.
“These data demonstrate the versatility, specificity and high level of efficiency of Sangamo’s ZFP genome-editing technology,” said Edward Lanphier, Sangamo’s president and CEO. “Although our initial clinical study is planned for beta-thalassemia, this same ZFP Therapeutic approach can be directly applied to related hemoglobinopathies such as sickle cell disease. We look forward to working with a team of world-renowned experts in this field, including the team at Children’s Hospital & Research Center Oakland, City of Hope and our colleagues at CIRM, to bring this treatment through IND application and into Phase 1 clinical testing.”
The abstract for this oral presentation (#434 -“Targeted Gene Modification In Hematopoietic Stem Cells: A Potential Treatment For Thalassemia and Sickle Cell Anemia”), along with a second Sangamo abstract (#433 – “Using Forced Chromatin Looping to Overcome Developmental Silencing of Embryonic and Fetal beta-Type Globin Genes In Adult Erythroid Cells”), were two of three studies highlighted at a press briefing organized by the American Society for Hematology.
Sangamo Abstracts at ASH Pertinent to Sangamo’s Programs in Hemoglobinopathies
Abstract#433– Using Forced Chromatin Looping to Overcome Developmental Silencing of Embryonic and Fetal Beta-Type Globin Genes in Adult Erythroid Cells
Oral Session 112: Thalassemia and Globin Gene Regulation: Targeted Engineering of Globin Gene Expression
Monday, December 9, 2013: 2:45 PM
Abstract#434– Targeted Gene Modification in Hematopoietic Stem Cells: A Potential Treatment For Thalassemia and Sickle Cell Anemia
Oral Session 112: Thalassemia and Globin Gene Regulation: Targeted Engineering of Globin Gene Expression
Monday, December 9, 2013: 3:00 PM
Abstract#2904 –Zinc Finger Nucleases Targeting the Beta-Globin Locus Drive Efficient Correction of the Sickle Mutation in CD34+ Cells
Session 801: Gene Therapy and Transfer: Poster II
Sunday, December 8, 2013, 6:30 PM-8:30 PM
Abstract#4213– Autologous Hematopoietic Stem/Progenitor Cell (HSPC) Therapy for Monogenic Blood Disorders: Scalable, cGMP-Compliant Process for Generating Highly Efficient Genome Edited HSPC
Session 801: Gene Therapy and Transfer: Poster III
Monday, December 9, 2013, 6:00 PM-8:00 PM
About SCD and Beta-Thalassemia
Mutations in the genes encoding globin, the oxygen carrying protein of red blood cells, lead to the hemoglobinopathies, sickle cell disease (SCD) and beta-thalassemia. The mutation giving rise to SCD causes the red blood cells to form an abnormal sickle or crescent shape, making them fragile and less able to deliver oxygen to tissues. They can also get stuck more easily in small blood vessels and break into pieces that can 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. Current standard of care is to manage and control symptoms, and to limit the number of crises. Treatments include blood transfusions, iron chelation therapy and administration of hydroxyurea, pain medications and antibiotics. The CDC currently estimates that there are 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, but generally the disorder results in excessive destruction of red blood cells leading to life-threatening anemia, enlarged spleen, liver and heart, and bone abnormalities. Cooley’s anemia (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 currently estimates that 1,000 people have Cooley’s anemia 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 research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase1/2 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.
SOURCE: Sangamo Biosciences
Post Views: 173
