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2015/02/13

Improving Gene Editing with Drugs: An Interview with Dr. Sheng Ding

CRISPR/Cas technology adapted from the bacterial immune system has received tremendous attention from medical research and technology community.  With the advent of genomic sequencing and subsequent disease predisposition gene discovery, this technology offers enormous opportunities to correct genetic defects for patients suffering from rare hereditary diseases currently with no effective therapy.  Although CRISPR/Cas technology is capable of precise genome editing, it is also well known for its low efficiency.  Recently, a report published in the latest issue of Cell Stem Cell from the laboratories of Dr. Ding Sheng, and his collaborator Dr. Lei Qi, co-senior author from the Stanford University,  have discovered a way to enhance the efficiency of CRISPR with the introduction of a few key chemical compounds. Dr. Sheng Ding is current the William K. Bowes, Jr. Distinguished Investigator and Professor at Gladstone Institute of Cardiovascular Disease, and Department of Pharmaceutical Chemistry, University of California San Francisco. Today, we sat down with Dr. Ding to hear his thoughts on CRISPR and the research findings. Your original interest is in stem cell research, what attracted you to CRISPR technology? Ding: Genome editing is an essential tool for conducting stem cell research, such as generating reporter cell lines, making isogenic iPSC lines for disease modeling, and performing genetic manipulation in stem cells to understand basic biology. In addition, stem cell is a great vehicle for many gene therapy approaches. It is quite natural to get into using CRISPR, which is much more convenient and powerful than previous genome editing techniques. Lastly, we are simply curious whether CRISPR mediated process could be modulated by small molecules, which is a central theme of what we do in research. Can you elaborate a bit more on your recent findings in the context of the power of CRISPR? Ding: Despite CRISPR technology is convenient and powerful, it is still at its infancy. Uncovering new ways to modulate its efficiency and precision, and better understanding its underlying mechanisms would be highly useful. Our recent work only scratched surface of it, and focused mostly on the precise editing of genome sequences through homology-directed repair (HDR), which is very inefficient. Through high throughput phenotypic screening of small molecules, we identified a couple of molecules that can significantly enhance the HDR-based high fidelity genome editing. Interestingly, we also identified inhibitors of HDR, which can enhance frame shift insertion and deletion mutations (for making sequence-specific gene knockout) mediated by non-homologous end joining (NHEJ). How do you see these new insight may be translated to drug discovery and clinic? Ding: Having more efficient CRISPR editing capability will certainly make it more useful for in vitro applications (such as making disease-specific cell lines for drug discovery). In addition, more precise control over CRISPR editing activity (e.g., turning it on and off) would potentially allow more safely deployment of CRISPR for therapeutic applications. Any insight regarding the opportunities to combine CRISPR and stem cell technologies to tackle major diseases? Ding: You are right that it is currently pursued by many researchers to combine CRISPR and stem cell technologies to tackle many untractable diseases. We are quite fortunate to be in the field and contribute our expertise.

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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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