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Site: http://news.yahoo.com/green/

A vector, which is used to transport the healthy gene into the patient's cells, is seen in this undated handout image provided by GlaxoSmithKline on April 1, 2016. REUTERS/Grant Thompson/GSK/Handout via Reuters More LONDON (Reuters) - The world's first life-saving gene therapy for children, developed by Italian scientists and GlaxoSmithKline, has been recommended for approval in Europe, boosting the pioneering technology to fix faulty genes. The European Medicines Agency (EMA) said on Friday it had endorsed the therapy, called Strimvelis, for a tiny number of children with ADA Severe Combined Immune Deficiency (ADA-SCID) for whom no matching bone marrow donor is available. Around 15 children a year are born in Europe with the ultra-rare genetic disorder, which leaves them unable to make a type of white blood cell. They rarely survive beyond two years unless their immune function is restored with a suitable bone marrow transplant. SCID is sometimes known as “bubble baby” disease, since children born with it have immune systems so weak they must live in germ-free environments. Strimvelis is expected to secure formal marketing authorization from the European Commission in a couple of months, making it the second gene therapy to be approved in Europe, after UniQure's Glybera, which treats a rare adult blood disorder. The U.S. Food and Drug Administration has yet to approve any gene therapies but a growing number of U.S. biotech companies, such as Bluebird Bio, have products in development. Other large pharmaceutical companies are also eyeing the field, including Bristol-Myers Squibb, which has a tie-up with UniQure. Research into gene therapy goes back a quarter of a century but the field has experienced many setbacks, including the high-profile death of an American patient in 1999 and some disastrous clinical trial results in the late 1990s and early 2000s. Now, though, optimism is building, helped by the discovery of better ways to carry replacement genes into cells. Martin Andrews, head of GlaxoSmithKline's rare diseases unit, believes the technology is proving itself, although it remains at an early stage of development. "We're on page one of chapter one of a new medicine text book," he told Reuters. A host of challenges still need to be overcome, including the complexity of delivering a product like GSK's new treatment, which requires bone marrow cells to be taken from the patient, processed and injected back. Trickiest of all may be pricing, given the tiny market for a therapy like Strimvelis. UniQure's Glybera made history in 2014 as the first drug to carry a $1 million price tag. GSK is not putting a price on its product but a source close to the company said that, if approved, Strimvelis would cost “very significantly less than $1 million”. GSK has several other gene therapies under development with researchers at Fondazione Telethon and Ospedale San Raffaele in Italy, including treatments for metachromatic leukodystrophy and Wiskott-Aldrich syndrome that could be submitted for regulatory approval in the next couple of years. Its Strimvelis treatment for ADA-SCID is also being lined up for submission to U.S. regulators, although Andrews said this would not happen before the end of next year.

Payen E.,CEA Fontenay-aux-roses | Payen E.,French Institute of Health and Medical Research | Colomb C.,CEA Fontenay-aux-roses | Colomb C.,French Institute of Health and Medical Research | And 9 more authors.
Methods in Enzymology | Year: 2012

Patients with β-thalassemia major require lifelong transfusions and iron chelation, regardless of the type of causative mutations (e.g., β 0, β E/β 0). The only available curative therapy is allogeneic hematopoietic transplantation, although most patients do not have an HLA-matched, geno-identical donor, and those who do still risk graft-versus-host disease. Hence, gene therapy by ex vivo transfer of a functional β-globin gene is an attractive novel therapeutic modality. In β-thalassemia, transfer of a therapeutic globin gene does not confer a selective advantage to transduced stem cells, and complex DNA regulatory sequences have to be present within the transfer vector for proper expression. This is why lentiviral vectors have proven especially suited for this application, and the first Phase I/II human clinical trial was initiated. Here, we report on the first gene therapy patient with severe β E/ β 0-thalassemia, who has become transfusion-independent, and provide methods and protocols used in the context of this clinical trial. © 2012 Elsevier Inc. All rights reserved. Source

Rojko J.L.,Charles River Pathology Assocts. | Evans M.G.,Pfizer | Price S.A.,Charles River Pathology Assocts. | Han B.,Pfizer | And 10 more authors.
Toxicologic Pathology | Year: 2014

Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans. © 2014 by The Author(s). Source

Abate-Daga D.,U.S. National Cancer Institute | Rosenberg S.A.,U.S. National Cancer Institute | Morgan R.A.,Bluebird Bio
OncoImmunology | Year: 2014

Pancreatic cancer remains largely an incurable disease necessitating the development of novel therapeutic approaches. Adoptive immunotherapy using chimeric antigen receptor (CAR)-transduced T cells represents an alternative treatment with curative potential. We present an overview of the engineering of novel CARs targeting prostate stem cell antigen (PSCA), implications for the development of immunotherapies, and potential strategies to circumvent ontarget/ off-tumor toxicities. © 2014 Landes Bioscience. Source

Negre O.,CEA Fontenay-aux-roses | Negre O.,French Institute of Health and Medical Research | Bartholomae C.,German Cancer Research Center | Beuzard Y.,CEA Fontenay-aux-roses | And 32 more authors.
Current Gene Therapy | Year: 2015

A previously published clinical trial demonstrated the benefit of autologous CD34+ cells transduced with a selfinactivating lentiviral vector (HPV569) containing an engineered β -globin gene (βA-T87Q-globin) in a subject with β - thalassemia major. This vector has been modified to increase transduction efficacy without compromising safety. In vitro analyses indicated that the changes resulted in both increased vector titers (3 to 4 fold) and increased transduction efficacy (2 to 3 fold). An in vivo study in which 58 β -thalassemic mice were transplanted with vector- or mock-transduced syngenic bone marrow cells indicated sustained therapeutic efficacy. Secondary transplantations involving 108 recipients were performed to evaluate long-term safety. The six month study showed no hematological or biochemical toxicity. Integration site (IS) profile revealed an oligo/polyclonal hematopoietic reconstitution in the primary transplants and reduced clonality in secondary transplants. Tumor cells were detected in the secondary transplant mice in all treatment groups (including the control group), without statistical differences in the tumor incidence. Immunohistochemistry and quantitative PCR demonstrated that tumor cells were not derived from transduced donor cells. This comprehensive efficacy and safety data provided the basis for initiating two clinical trials with this second generation vector (BB305) in Europe and in the USA in patients with β -thalassemia major and sickle cell disease. © 2015 Bentham Science Publishers. Source

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