Landmark article
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Blood. 2015 Apr 23;125(17):2597-604. doi: 10.1182/blood-2014-12-615948. Epub 2015 Mar 2.
Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells.
Hoban MD1, Cost GJ2, Mendel MC2, Romero Z1, Kaufman ML1, Joglekar AV1, Ho M1, Lumaquin D1, Gray D1, Lill GR1, Cooper AR3, Urbinati F1, Senadheera S1, Zhu A2, Liu PQ2, Paschon DE2, Zhang L2, Rebar EJ2, Wilber A4, Wang X5, Gregory PD2, Holmes MC2, Reik A2, Hollis RP1, Kohn DB6.
Abstract
Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the β-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the β-globin locus with minimal off-target modification. By codelivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34(+) hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rγ(null) mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34(+) cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers.
Editorial by James Eckman MD: |
Sickle cell anemia is the first “molecular disease” defined by Linus Pauling in 1949.1 Considerable progress has been made in understanding this disease and in defining the genetic basis for this and many other diseases. The human genome project and many other basic studies in molecular genetics have led to development of tools now used to diagnose and treat these genetic disorders. This month’s Sickle Cell Update highlights an important report from the journal Blood that presents exciting progress in using these new tools to develop a cure for sickle cell disease in the not too distant future.2 Hoban et al. report the ability to snip out the DNA that contains the sickle mutation and insert the normal DNA sequence, thereby, correcting the mutation in human hematopoietic stem and progenitor cells with relatively high efficiency and excellent specificity. The modified stem cells from bone marrows of individuals with sickle cell anemia are able synthesize normal hemoglobin in culture to a level of about 20%. They also show that such genetically modified cells are able to be transplanted successfully into immune-deficient mice, although levels of hemoglobin synthesis are not as robust. The same issue of Blood also contains an excellent editorial that highlights the accomplishments of this research and discusses the limitations of the results in terms of curing sickle cell disease.3
Although there are still many obstacles ahead, it appears that molecular genetic surgery offers promise as a true cure for sickle cell disease. Increasing the percentage of hematopoietic stem cells corrected and growing them is large enough numbers to use for human bone marrow transplantation remain challenges. Once these are overcome, marrow could be removed from an individual, stem cells isolated, and the mutation corrected. These correct stem cells could then be grown to sufficient numbers and used to cure the individual with a marrow transplant using the individual’s own corrected stem cells. Perhaps in the near future our goal of making sickle cell the first molecular disease cured in all individuals will be realized because of the great advances in molecular genetic research.
References:
1. Pauling L et al. Sickle cell anemia. A molecular disease. Science 1949;109:443.
2. Hoban et al. Correction of the sickle cell mutation in human hematopoietic stem/progenitor cells. Blood 2015;125:2597.
3. Tolar J. Sickle cell and silent spleen. Blood 2015;1125:2589.
Proportion of Adults With Sickle Cell Anemia and Pain Crises Receiving Hydroxyurea Nicolas Stettler, MD, MSCE1; Colleen M. McKiernan, MSPH1; Court Q. Melin, BS1; Oluwakayode O. Adejoro, MD, MPH1; Nancy B. Walczak, PhD, FSA1
Few American adults with sickle cell anemia are getting a recommended medication that can help them manage pain, breathing problems and other debilitating symptoms, according to a new study. Using a national database, researchers found that less than one-quarter of sickle cell patients who should have been taking a drug called hydroxyurea actually were.
“This is a medication that’s highly beneficial and yet most people aren’t getting it,” said George Buchanan, MD, a sickle cell expert, and a professor at the University of Texas Southwestern Medical Center at Dallas, who was not involved in the new study.
PhenX Toolkit Seeks Comments
The Toolkit provides standard measures related to complex diseases like sickle cell disease, phenotypic traits and environmental exposures. Use of PhenX measures facilitates combining data from a variety of studies, and makes it easy for investigators to expand a study design beyond the primary research focus. All Toolkit content is available to the public at no cost.
Information about the project is available at www.phenx.org The National Human Genome Research Institute (NHGRI) awarded RTI International a four-year cooperative agreement to expand and enhance the PhenX Toolkit at https://www.phenxtoolkit.org/
An important aim of this grant is to review the measures in the 21 research domains after receiving input from the scientific community.
Please take a few minutes to review the measures in these PhenX domains: Demographics, Environmental Exposures, and Social Environments. Your rating (number of stars) should reflect how useful this protocol is to your work and its relevance to the PhenX Toolkit. We tried to make it easy for you to rate the measures you are familiar with; you do not have to rate all of them. Please click Review PhenX Toolkit Measures to rate and comment on these measures.
PhenX will be collecting input on these measures from May 5 - May 18, 2015. Responses collected during this time will be summarized for consideration by an Expert Review Panel.
This is an opportunity to tell PhenX what you like about these measures, what could be better, and suggest improvements!
Comments needed from the Sickle Cell Community from Centers for Medicare and Medicaid Services (CMS)
Early in 2015, the American Society for Blood and Marrow Transplantation (ASBMT) and the National Marrow Donor Program (NMDP) submitted a formal request to the Centers for Medicare and Medicaid Services (CMS) for expansion of the current list of diseases for which Hematopoietic Cell Transplant (HCT) is expressly noted as covered and reimbursable. Several disease categories were included in this request, including Myelofibrosis, Sickle Cell Disease, Lymphoma and Multiple Myeloma.
CMS has agreed to open a National Coverage Analysis (NCA) for two of these disease indications now – Sickle Cell Disease and Myelofibrosis – and they have indicated that they will review the remaining indications sequentially. There is a public comment period open from April 30 – May 30, 2015. Information on how to make a comment is described below.
The NMDP and ASBMT submitted a coverage request for these indications due to an identified barrier to care created by the lack of coverage clarity for these disease indications when treating Medicare patients. Currently, Medicare does not indicate that these indications are either covered or non-covered (with the exception of Myeloma) and does not allow Medicare Administrative Contractors (MACs) to provide pre-authorization for HCT. This lack of a clear national coverage decision places the Medicare beneficiary, and the transplant program treating them, at severe financial risk if the MAC denies the reimbursement claim after the procedure is complete. Our recent experience seeking coverage clarity for HCT for Myelodysplastic Syndromes (MDS) has clearly demonstrated this access barrier and the effect of its removal; the clarity of coverage provided through the Medicare study for MDS has allowed patients to receive the care they need. The request letter submitted by our organizations this January provides additional information on the barriers created by this lack of coverage clarity.
While Medicare primarily serves individuals aged 65 years and older, approximately 15% of those covered are younger adults who have a disabling illness, such as sickle cell disease1. The coverage policies set by Medicare are often used as a benchmark reference for coverage by other payers and insurance plans, including state Medicaid programs.
How you can help: Please visit the Medicare website on this topic, read the materials and follow the instructions on how to submit a comment. You can submit a comment on the CMS website. This system does not accept attachments. If you wish to include an attachment please email it to CAGinquiries@cms.hhs.gov. Please include “NCA for SCT/HCT: CAG-00444R” in the subject line of your email.
Awards
Samir K Ballas, MD, FACP, Emeritus Professor of Medicine,Thomas Jefferson University was selected as the 2015 recipient of the American Academy of Pain Medicine (AAPM) Patient Advocacy Award. The Award was presented during the AAPM Awards Presentation on Saturday, March 21:
The Patient Advocacy Award recognizes activity of an individual in advocating for appropriate evaluation and treatment of patients suffering from pain. This award was created to honor those healthcare professionals whose deeds reflect their recognition of the importance and impact of the specialty of Pain Medicine. The Academy recognizes only a few individuals for their outstanding contributions to the field of Pain Medicine each year. Dr. Ballas has been a long time advocate for excellent pain management in sickle cell patients.
Lillie Johnson - advocate for sickle cell anemia education in Toronto CA
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