New research presented at the 55th annual meeting of ASH?, the American Society of Hematology, being held in New Orleans, Louisiana, USA, from December 7 – 10, 2013,uncovers several important insights into the pathophysiology of sickle cell disease and thalassemia that may soon translate into the development of better, more targeted treatments for hundreds of thousands of patients worldwide.
Sickle cell disease or SCD is an inherited, chronic disorder affecting nearly 100,000 Americans. Instead of producing healthy red blood cells, individuals with the disease produce abnormal hemoglobin, a protein that attaches to oxygen in the lungs and carries it to all parts of the body. This abnormal hemoglobin causes the red blood cells to become rigid and sickle-shaped, which then block blood and oxygen flow to the body and lead to intense pain and infections. Thalassemia, the name for a family of chronic blood disorders characterized by low hemoglobin production, also affects the blood?s ability to transport oxygen and is associated with life-threatening complications.
New insights leading to new targeted treatments
While there are several ways to treat sickle cell diseaseand thalassemia, current options only manage symptoms and do not correct the underlying genetic defects associated with these disorders. Fortunately, medical researchers and clinical investigators continue to uncover important insights related to the pathophysiology of these blood disorders and their symptoms. What they uncover is fueling the development of new targeted interventions that may lead to improved treatments. The findings presented at the55th annual meeting of ASH?, the American Society of Hematologyexplore a promising potential pain management treatment for sickle cell diseasepatients as well as two strategies that use natural proteins to activate the gene responsible for the production of healthy hemoglobin.
?We now know a great deal about the causes of sickle cell disease and thalassemia and how to treat many of the complications. However, we desperatly need new insights and care strategies that can allow for better management of these diseases,? said John Tisdale, MD, Senior Investigator of the Molecular, Clinical, and Hematology branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health in Bethesda, MD, USA. ?Exciting new developments being reported include a new therapy that could help sickle cell patients better manage pain crises and two new gene therapy strategies that could allow patients with both sickle cell disease and thalassemia to produce healthy hemoglobin. These advances bring us one step closer to achieving our goal of improving the long-term outlook and enhancing the quality of life of patients with these serious disorders.?
This ? signals a major breakthrough …we have increased our understanding of how these debilitating crises develop? but have not been able to intervene once they happen. This potential new drug would change that.
Not attacking the root cause
Vaso-occlusive crisis (VOC) is a common and painful complication of sickle cell disease that occurs when sickled red blood cells and white blood cells stick to the lining of blood vessels, blocking blood flow and preventing oxygen from reaching parts of the body. Sickle cell patients experiencing VOC typically receive potent drugs to alleviate intense pain, but these medications only manage the symptoms and do not attack the root cause of the crisis. Previous research has suggested that molecules called selections or glycoprotein cell adhesion molecules implicated in inflammatory processes, are involved in cell-to-cell adhesion and may be a significant driver of VOC. Recent studies of a new selectin inhibitor compound GM-1070, a synthetic glycomimetic molecule being developed by GlycoMimeticsin partnership with Pfizer, have demonstrated efficacy in reducing VOC in animal model. The trial drug inhibits all three selection types — E-selectin, L-selectin and P-selectin — required to achieve adequate therapeutic activity in certain inflammatory disorders.[1]
To test the safety and efficacy of GMI-1070 in SCD patients, investigators conducted a Phase II trial of the drug, randomizing 76 patients (ages 12-51) experiencing VOC to receive up to 14 doses of either GMI-1070 or placebo. All treated patients reached the primary endpoint of resolving their VOC. While VOC typically lasts five to seven days, VOC episodes in patients who received GMI-1070 in the study were two to three days shorter than in those who received placebo. Furthermore, patients who received GMI-1070 required significantly less narcotics during their VOC compared to the patients randomized to placebo. In the study, 18 patients discontinued treatment (nine in each patient group) due to adverse events, no improvement at day five, or other reasons, and total adverse event rates were comparable between the groups.
Researchers believe that GMI-1070?s ability to inhibit all selections offers a distinct advantages over other approaches that target only one selectin, or which are so broadly active as to be non-specific.?If this drug continues to demonstrate efficacy in our ongoing studies, it would be the first drug to actually interrupt the mechanism of VOC,? noted lead study author Marilyn J. Telen, MD, of Duke University Medical Center in Durham, N.C. ?This would signal a major breakthrough since, even though we have increased our understanding of how these debilitating crises develop, we have not been able to intervene once they happen. This potential new drug would change that.?
Switching from adult to fetal hemoglobin
Humans produce different types of hemoglobin ? the protein responsible for delivering oxygen in the body ? at different points in development. In utero, the human fetus produces fetal hemoglobin. Around the time of birth, newborns begin producing adult hemoglobin. In patients with sickle cell disease and ??thalassemia, the gene that encodes for the production of adult hemoglobin is mutated. In sickle cell disease, red blood cells take on a characteristic sickle shape, stick together, and block the flow of blood and oxygen through small blood vessels resulting in painful complications. Patients with ??thalassemia do not make red blood cells efficiently, requiring lifetime blood transfusions and in most cases ongoing treatment for transfusion related complications such as iron overload. While these patients? adult hemoglobin is defective, their fetal hemoglobin gene is perfectly normal and prevents both sickle cell diseaseand ??thalassemia until it is switched off during development. Stimulating the switch from adult back to fetal hemoglobin to compensate for defective adult hemoglobin represents an attractive therapeutic strategy for both diseases. [2]
Zinc Finger Nucleases or ZFNs
Researchers have begun to explore highly targeted approaches to switch off production of defective adult hemoglobin and, instead, switch on the gene responsible for producing normal fetal hemoglobin in patients with sickle cell diseaseand ??thalassemia. In a recent study presented this year at the annual meeting of the American Society of Hematology, investigators used a naturally occurring class of protein called zinc fingers to generate specially designed zinc finger nucleasesor ZFNs targeting specific genes involved in the switch from fetal to adult globin synthesis. They hypothesized that the ZFNs could be used to change the genetic sequence of the hematopoietic or blood-forming stem cells or HSCs fro
m sickle cell diseaseor ??thalassemia patients and enable them to produce normal fetal hemoglobin. In their laboratory, investigators delivered the ZFNs into human HSCs and observed both in the case of sickle cell diseaseand ??thalassemia that fetal hemoglobin production increased. Investigators then scaled up this approach on a large preparation of HSCs sufficient to treat a patient and observed an identical outcome, suggesting that this approach may be ready for human trials. Finally, investigators transplanted the corrected cells into mice, and observed that they differentiated in to the expected blood cell types and remained present in the mice at all study points tested, verifying their ability to survive and function as a source of new blood cells in the body.[3]
?The idea of engineering natural proteins to change the gene sequence of hematopoietic stem cells to allow for the production of normal hemoglobin in patients with sickle cell disease and ?-thalassemia is enormously exciting,? said lead study author Fyodor Urnov, PhD, of Sangamo Biosciencesin Richmond, CA, USA. ?The fact that we can use the same approach to address both diseases highlights the significant potential of this approach to help many people worldwide.?
Activating hemoglobin production
A potential strategy for replacing unhealthy adult hemoglobin with healthy fetal hemoglobin in patients with sickle cell disease and ?-thalassemia takes advantage of a normal process called chromatin looping. This processtakes place when the locus control regionor LCR, a cluster of regulatory DNA elements, physically contacts genes that activate hemoglobin production via a looping mechanism and turns them on.[4]
In one particular study, Jeremy W Rupon, MD, PhD,Gerd A. Blobel, MD, PhDand co-investigators from the Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA, sought to direct this chromatin loop away from the adult globin genes and instead turn on fetal globin genes to stimulate the production of normal fetal hemoglobin. Elevated levels of fetal hemoglobin have long been known to ameliorate the clinical course of sickle cell diseaseand some forms of ?-thalassemia. Using synthetic proteins called zinc fingers (ZFs), these investigators redirected the chromatin loop to activate embryonic globin genes in mice and fetal globin genes in humans. The researchers specifically designed ZFs that would bind to the part of the LCR that initiates embryonic gene transcription, fused them to protein elements previously known to be involved in chromatin loop formation, and introduced them into an adult mouse red blood cell line that normally produces nearly 100% adult ? globin. This led to marked activation of embryonic globin production that was dependent on chromatin looping. The researchers then extended the same approach to human ?-globin locus in an effort to activate expression of the fetal ?-globin gene in adult erythroid cells. The researchers used ZFs to create a chromatin loop connecting the fetal globin genes with the LCR. This led to a striking increase in fetal globin, accounting for nearly 90% of total globin production.
?We have opened up a new potential therapeutic avenue by forcing chromatin loops to increase fetal hemoglobin production so it overtakes existing mutated adult hemoglobin,? explained Blobel, the study’s primary investigator. ?There is a tremendous interest in this field to raise fetal globin genes in people who have sickle cell disease or certain forms of ?-thalassemia, which can significantly improve their condition.?
For more information:
[1] Telen MJ, Wun T, McCavit TL, De Castro LM, Krishnamurti L, Lanzkron S, Hsu LL, et al. GMI 1070: Reduction in Time to Resolution of Vaso-Occlusive Crisis and Decreased Opioid Use in a Prospective, Randomized, Multi-Center Double Blind, Adaptive Phase II Study in Sickle Cell Disease. [Abstract]
[2] Reik A, Chang KH, Stehling-Sun S, Zhou Y, Lee GK, Truong L, Wood T, Zhang Z, et al. Targeted Gene Modification in Hematopoietic Stem Cells Using Zinc Finger Nucleases (ZFNs): A Potential Treatment for Thalassemia and Sickle Cell Anemia [Abstract]
[3] Carroll D.Genome engineering with zinc-finger nucleases. Genetics. 2011 Aug;188(4):773-82. doi: 10.1534/genetics.111.131433. [Article][PubMed]
[4] Rupon JW, Deng W, Wang H, Gregory PD, Reik A, Dean A, and Blobel GA. Using Forced Chromatin Looping to Overcome Developmental Silencing of Embryonic and Fetal ?-Type Globin Genes in Adult Erythroid Cells. [Abstract]
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