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2015/02/05

Gene Therapy Offers Potentially New Treatment for beta-Thalassemia Patients

Bluebird Bio Inc., a leading gene therapy biotech company based in Cambridge, Massachusetts, announced on February 2 that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to one of its investigational drugs, LentiGlobin® BB305 for the treatment of transfusion-dependent patients with beta-thalassemia major. Beta-thalassemia is a rare genetic disease affecting 40,000 newborn children annually worldwide.  It is caused by mutations in the beta-globin gene (HBB).  HBB encodes beta chains of hemoglobin and mutation of this gene causes different types of rare blood genetic diseases (Sickle Cell disease or beta thalassemia).  Depending on the severity of symptoms, beta-thalassemia is clinically divided into two types: thalassemia major and thalassemia intermedia with thalassemia major being more severe. Presently, the existing treatment options for these patients have significant side effects and limitations. LentiGlobin BB305 developed by Bluebird Bio utilizes an improved lentiviral vector to insert a correct copy of human beta-globin gene into the patient’s own hematopoietic stem cells ex vivo and then transplanting those modified cells into the patient through infusion into the bloodstream.  LentiGlobin BB305 is currently undergoing three clinical trials globally aimed at treating both beta-thalassemia and sickle cell disease.   Related links: http://ghr.nlm.nih.gov/condition/beta-thalassemia http://ghr.nlm.nih.gov/condition/sickle-cell-disease http://www.bluebirdbio.com/product-overview.php

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2015/02/05

A New Weapon to Fight Breast Cancer

Congratulations to Pfizer for receiving accelerated approval for its investigational new drug, IBRANCE to treat advanced breast cancer from the U.S. FDA on February 3.  IBRANCE is an inhibitor of cyclin-dependent kinase 4/6 (CDK4/6) involved in promoting the growth of cancer cells. IBRANCE is the first CDK4/6 inhibitor approved by the FDA to treat cancer. Breast cancer in women is the second most common type of cancer in the US.  According to the American Cancer Society, about 231,840 new cases of invasive breast cancer will be diagnosed in women and about 40,290 women will die from breast cancer in 2015 in the US.  Worldwide, breast is one of the 5 most common sites diagnosed with cancer. IBRANCE is intended to treat postmenopausal women with estrogen receptor-positive and epidermal growth receptor 2-negative (ER+/HER2-) metastatic breast cancer.  This group of patients represents the largest proportion of breast caner cases, and “This approval represents the first treatment advance for this group of women in more than 10 years,” said Mace Rothenberg, the head of oncology for Pfizer. IBRANCE was reviewed and approved under the FDA’s Breakthrough Therapy designation and Priority Review programs. “IBRANCE is the first CDK4/6 inhibitor approved by the FDA to treat cancer,” commented Qunsheng Ji, Vice President of Oncology at WuXi.  “This represents a significant advance in bridging basic biology with patient benefit, and exemplifies the importance of understanding of the disease in developing innovative medicine for cancer treatment.  The success of IBRANCE also represents the outcomes of collective and persistent efforts on scientific researches and drug discovery in cell cycle fried over the last two decades.”

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2015/02/01

BCX4161, a Promising New Orally Administered Drug for the Rare and Genetic Disorder Hereditary Angioedema, Received Fast Track Status from the FDA

BioCryst Pharmaceuticals, Inc., a small pharmaceutical company headquartered in Durham, North Carolina announced on January 26 that one of the drugs in the company’s pipeline, BCX4161 has been granted fast track status by the FDA. BCX4161 is a novel and selective inhibitor of plasma kallikrein discovered by BioCryst and is in development for the treatment of hereditary angioedema (HAE). HAE is a rare and hereditary disease affecting approximately 1 in 10,000 to 1 in 50,000 people.  The gene responsible for HAE is called C1-inhibitor (C1NH).  HAE patients suffer episodic attacks of edema in various parts of the body including hands, feet, face and airway.  In addition, patients often have bouts of excruciating abdominal pain and other GI track symptoms due to intestinal edema.  Severe airway edema can lead to death by asphyxiation.  BCX4161 inhibits plasma kallikrein and consequently suppresses bradykinin production. Bradykinin is the mediator of acute swelling attacks in HAE patients. Current treatment options include purified C1 inhibitor concentrate (Cinryze, Berinert, or Ruconest), Ecallantide (a kallibrein inhibitor) and Icatibant (a bradykinin B2 receptor antagonist).  These drugs are in either intravenous or subcutaneous injection form with various adverse effects.  BCX4161 is being developed as an orally administered drug and has the potential to significantly improve HAE patient treatment and their quality of life.   Related Links: http://www.haea.org/patients/what-is-hae/ http://www.omim.org/entry/106100

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2015/01/22

First Crystal Structure of Human GLUT1 Solved

An article published in the prestigious Nature magazine this summer by a group led by one of a 2012 recipient of WuXi Life Science and Chemistry Awards, Dr. Nieng Yan of Tsinghua University, made a great contribution toward the understanding of GLUT1 functions and implications in disease intervention by solving the first crystal structure of human GLUT1.  The article is titled “Crystal structure of the human glucose transporter GLUT1” (Nature 510, 121-125, PMID: 24847886). Glucose is the essential energy source for human cell metabolism.  To transport glucose across the plasma membrane, cells reply on a family of membrane proteins called glucose transporters (GLUTs), encoded by solute carrier 2A gene family (SLC2A).  These transporters allow glucose uptake across the plasma membrane through facilitative diffusion.  Fourteen members have been identified in this family of glucose transporters and they are responsible for glucose uptake in different cell types and tissues in humans.  Glucose homeostasis is vital for metabolism supplying energy source for essential cellular functions via respiration, and providing building blocks and reducing power required for cellular growth and proliferation via several well-characterized biochemical pathways.  Perturbation of glucose uptake causes many diseases. GLUT1 (glucose transporter 1) is one of the members of GLUT family.  It is mainly expressed in erythrocytes and in the endothelial cells of blood-tissue barrier, such as blood-brain barrier and placenta.  Mutations in GLUT1 cause several rare hereditary diseases including GLUT1 deficiency syndrome 1 and 2, Dystonia 9, and idiopathic generalized epilepsy-12.  Disregulation, mainly over-expression of GLUT1 is associated with a number of cancers, cancer progression and poor prognosis.  Therefore, characterizing the structure of GLUT1 and deciphering the mechanisms involved in regulation of glucose transport would provide structural basis for understanding the physiology and pathophysiology of glucose uptake-associated functions and diseases. Although structures of homologous GLUT1 from bacteria have been solved, these GLUT1 transporters are proton-driven symporters.  Human GLUT1 is a proton-independent uniporter that transport glucose down its concentration-gradient through facilitative diffusion.  This paper provided the first crystal structure for a uniporter GLUT1.  According to the paper, “Structure resolution of the human GLUT1 serves as a framework for understanding its functional mechanism.”  By comparison to the structures reported for bacterial GLUT1, insights regarding the differences between proton-driven active versus facilitative diffusion could be gained and be applicable to similar uniporters. There are practical implications from this work as well.  For instance, by mapping variants observed in GLUT1 on to the crystal structure, functional consequence could be deduced providing support to classification of genetic variants and diagnosis of rare diseases associated with GLUT1 mutations.  GLUT1 is one of the members of glucose transporters whose expression is frequently upregulated in malignant cancers to increase glucose uptake to support malignant growth and proliferation.  Crystal structure of GLUT1 will provide clues for therapeutic development aiming at either blocking the transporter or utilizing the transporter to deliver chemotherapeutic drugs.  As the authors stated, “the structure also serves as a guiding principle for the development of potential therapeutic agents that target GLUT1 and other physiologically important MSF (major facilitator superfamily) sugar transporters.”  In addition, GLUT1 has been shown to interact with the receptor-binding domains of the human T-cell leukemia virus (HTLV)-1 and -2 envelope glycoproteins.  The crystal structure resolution of GLUT1 could also result in novel therapeutic interventions for HTLV infections.

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2015/01/22

Antibodies Designed to Combat Ebola May Provide Protection from the Rare but Deadly Infection

New insights about experimental monoclonal antibody cocktails that recognize Ebola virus may soon help provide an effective treatment option.  Ebola virus disease (EVD) is a highly lethal illness in humans that is sometimes associated with bleeding. It is caused by a family of viruses (Filoviridae, genus Ebolvirus) linked to hemorrhagic fever. No approved medications exist to prevent or treat EVD. Investigators from The Scripps Research Institute (TSRI) and Mapp Biopharmaceuticals are developing 3 different monoclonal antibody (mAb) cocktails (or mixtures) that bind to Ebola virus and limit its spread to healthy cells. In past outbreaks—affecting mainly small, isolated human populations in African countries—the mortality rates ranged from 30 to 90%1,2. Currently, the 2014 outbreak in Western Africa is the largest on record, with more than 15,000 confirmed infections and 5,400 deaths as of November 20143. The experimental Ebola antibody cocktails, MB-003 and ZMAb have shown success in treating non-human primates. A small supply of ZMapp—the most effective of the 3 experimental therapies — was exhausted after treating 6 medical and religious workers (some of whom died) that contracted EVD1, 4. New information about the rationale for how the cocktails work may aid in developing a much needed treatment option; however, well-designed clinical trials must ultimately determine ZMapp efficacy. Dr. Charles Murin of TSRI and co-authors reported their findings in the October 2014 issue of the Proceedings of the National Academy of Sciences. 1 The researchers used electron microscopy and other methods to compare structural features and Ebola-specific binding capabilities of the antibody cocktails MB-003, ZMAb, and ZMapp.1 The results showed the antibodies fall into 3 groups based on the vulnerable viral region they bind (specifically, the mucin-like domain, the glycan cap, or the core glycoprotein). Analyses also revealed that while each of the cocktails contain some unique components, redundancies exist, and in some cases, the cocktails contain antibodies that compete for overlapping regions of the virus. It is hopeful that the new study will help identify the components of the cocktails that most effectively target distinct regions of the virus and aid in developing enhanced drug formulations. Fortunately, ebolavirus mutations thus far detected in Guinea and Sierra Leone have not altered the sites of the Ebola virus that are recognized by the ZMapp antibodies1—indicating that new supplies of ZMapp “would likely have efficacy against viral strains circulating in the ongoing 2014 outbreak.” The authors note, “This work provides clear next steps to determine if ZMapp can be honed for even greater potency, efficacy, or production.” This work by Murrin and colleagues provides direction for strategically selecting next-generation antibody cocktails that may be effective against existing ebolaviruses and mutated viral variants.1   References:   1Murin, C.D., Fusco, M.L., Bornholdt, Z.A., et al. 2014. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proceedings of the National Academy of Sciences doi:10.1073/pnas.1414164111. 2World Health Organization. http://www.who.int/mediacentre/factsheets/fs103/en/. Accessed November 20, 2014. 32014 Ebola Outbreak in West Africa. http://www.cdc.gov/vhf/Ebola/outbreaks/2014-west-africa/index.html. Accessed November 20, 2014. 4Judging An Ebola Drug In The Middle Of A Crisis. http://www.kpbs.org/news/2014/aug/21/evaluating-san-diego-companys-ebola-drug-amidst-cr/. Accessed November 20, 2014. 5Detailed Picture Of ZMapp Shows Room For Improvement. http://www.kpbs.org/news/2014/nov/18/detailed-picture-zmapp-shows-room-improvement/. Accessed November 20, 2014.    

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