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Human Gene TherapyVol. 21, No. 2 Free AccessThe Digest/The WirePublished Online:17 Feb 2010https://doi.org/10.1089/hum.2010.2021AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Chaperoning β-thalassemiapage: 149In adult humans, hemoglobin is found as a tetramer consisting of two α and two β subunits that are noncovalently bound. Hemoglobin chain imbalance leads to hemoglobinopathies such as β-thalassemia, wherein deficient or altered synthesis of β-globin causes the intracellular precipitation of excess α-globin chains and ineffective erythropoiesis. There is presently no curative therapy for the most severe form (called β-thalassemia major) other than allogeneic hematopoietic stem cell transplantation. Genetic correction of autologous hematopoietic stem cells has been examined as an attractive alternative to bone marrow transplantation. This approach relieves the need for a compatible donor and eliminates the risks of graft-versus-host disease and graft rejection associated with allogeneic bone marrow transfer. Several groups have shown that transplantation of autologous bone marrow cells transduced with lentiviral vector carrying wild-type β-globin gene results in elevated hemoglobin production and correction of anemia in animal models of β-thalassemia major; this approach is currently undergoing clinical testing in France with another trial soon planned for the United States.1 In this issue of Human Gene Therapy, Wang and colleagues in the laboratory of Dr. Jingzhi Zhang at the Shanghai Institute of Medical Genetics explore an alternative to gene replacement therapy. The authors reason that because β-thalassemia major results from excess α-globin, transfer of a gene encoding a chaperone protein called α-hemoglobin stabilizing protein (AHSP) should neutralize excess α-globin subunits and help to relieve symptoms of β-thalassemia. Using a transgenic approach, Wang and colleagues demonstrate that expression of AHSP partially relieves some of the pathology in affected β-thalassemic mice, including splenomegaly. Although the strategy appears to be less efficient than β-globin gene replacement therapy, this study confirms the importance of AHSP in α-globin synthesis and the development of β-thalassemia. (sk)An Eye for Sendaipage: 199The aspirational goal of in vivo gene therapy is high efficiency and specificity of target cell transduction. One approach to accomplish this is to provide extended residence time for the vector in close proximity to the cell type of interest. The situation is no different for gene therapy approaches in the eye, as was shown in the recent clinical success in the treatment of an inherited blindness named Leber's congenital amaurosis (LCA). In this application, vector is delivered to the subretinal space. The vector solution is deposited between the retinal epithelial layer (RPE) and the neuronal retina by interrupting their interconnectivity and creating a subretinal space. This elevation of the retina created by the procedure dissipates gradually in the first 24 hours after injection. The two flanking cell types of the subretinal space, the RPE and the photoreceptors, are both relevant targets for gene therapy.In this issue of Human Gene Therapy, Murakami and colleagues tackle the concern that prolonged subretinal detachment due to the presence of the vector volume delivered by subretinal injection may be harmful. Indeed, there has been some indication that retinal thinning occurs after this procedure, but overall the procedure is deemed safe. The concern remains, however, that the procedure leads to the neuronal retina being deprived of trophic and metabolic factors provided by the RPE and choroid. The authors, however, acknowledge the necessity to bring vector and target into close proximity in order to achieve high-level functional transduction. With this as their main objective, they evaluate pseudotypes of lentivirus-based vectors in in vitro and in vivo models of RPE transduction.The data indicate that the Sendai pseudotype achieves similar levels of transduction when vector is removed shortly after inoculation versus when it is left on the cells. Their interesting approach in vivo allows, with residence time of only 5 minutes, the achievement of functionally significant levels of transduction, after which vector is aspirated and the subretinal space is collapsed. The authors demonstrate the efficacy of this optimized procedure in a laser-induced choroidal neovascularization murine model for age-related macular degeneration by gene transfer of the antiangiogenic factors soluble Fms-like tyrosine kinase-1 (sFlt-1) and human pigment epithelium-derived factor. (lhv)141Regulatory wireOrphan Drug Designations SoarA new study conducted by the Tufts Center for the Study of Drug Development (CSDD) reports that the number of orphan product designations in the United States has more than doubled during the last decade, reflecting growing interest by pharmaceutical and biotech companies in developing products to treat orphan diseases.1The U.S. Orphan Drug Act of 1983 was passed with the objective of encouraging pharmaceutical companies to develop drugs for diseases that have a small market. Officially, the Act defines an orphan disease as one with a prevalence rate of fewer than 200,000 individuals in the United States (see inset). The National Institutes of Health estimates that there are more than 7000 orphan diseases affecting approximately 25 million people in the United States. Under the law, companies that develop an orphan drug may sell it without competition for 7 years, and may get clinical trial tax incentives among other benefits. Market exclusivity under the Act, however, differs from that of a traditional product or process patent in several ways. Coverage is narrower than with a patent; it applies only to orphan drug use for the rare disease for which it was approved. During the 7-year-period of market exclusivity, a second sponsor could apply for, and receive, market approval for the exact same drug for any other use (i.e., use other than treatment of the initially approved rare disease), including the treatment of a different rare disease. Furthermore, unlike a patent, the “exclusivity” granted a manufacturer is limited by the Act if the original sponsor is unable to meet the demand for the drug, decides to cease drug production, or consents to “shared exclusivity” with another supplier. In these circumstances, the Secretary of the Department of Health and Human Services may permit a second company to market the nonpatented orphan drug to ensure a continuous, adequate supply of necessary medications.2According to the CSDD report, since 1983 more than 2000 products in development have been designated as orphan drugs, with the U.S. Food and Drug Administration (FDA) granting market approval to 350 drugs and biologics. Before 1983 fewer than 10 such orphan drug products were on the market. Over the last decade, orphan products comprised 22% of all new molecular entities (NMEs) and 31% of all significant biologics (SBs) receiving U.S. marketing approval. The CSDD report notes that orphan drug developers had a higher rate of clinical approval compared with mainstream drug makers, with 22 and 16% success rates, respectively. Among the orphan products that have been developed since 1983 are drugs for glioma, multiple myeloma, cystic fibrosis, and phenylketonuria. Dr. Christopher-Paul Milne, Associate Director of the CSDD, commented in a press release that “the Orphan Drug Act, without question, can be considered a success. It has been emulated throughout the world, and today Japan and Europe have similar programs, while Singapore and Australia give special allowance for the importation and marketing approval of orphan products approved in the U.S.”Yet, some critics have questioned whether orphan drug legislation was the real cause of the increase in orphan disease treatments (claiming that many of the new drugs were for disorders that were already being researched anyway, and would have had drugs developed regardless of the legislation), and whether the Orphan Drug Act has really stimulated the production of truly nonprofitable drugs. The Act has also received some criticism for allowing some pharmaceutical companies to make a large profit off drugs that have a small market but still sell for a high price.3,4Regardless of these criticisms, the global orphan drug market continues to grow and is expected to reach $81.8 billion by 2011. Biologics account for more than 60% of the orphan drug market and are expected to reach annual sales of $53.4 billion by 2011.5 (sk)What Is an Orphan Disease?There is no universal definition for what constitutes an orphan disease. The term has been used to describe diseases that are neglected by doctors (e.g., Fabry's disease, alveolar echinococcosis, etc.) or, more commonly, the term orphan disease is used to designate diseases that affect only small numbers of individuals (health orphans).In the United States, an orphan disease is officially defined as one with a prevalence of fewer than 200,000 individuals, but in Japan the number is 50,000 and in Australia it is 2000. In the European Union (EU), an orphan disease is one that affects fewer than 5 people per 10,000 and includes some neglected tropical diseases that are found primarily in developing nations. The EU legislation, administered by the Committee for Orphan Medicinal Products of the European Medicines Agency (EMEA), grants 10 years of market exclusivity. In an effort to reduce the burden on manufacturers applying for orphan drug status, the FDA and EMEA agreed in late 2007 to use a common application process for both agencies. However, the two agencies continue to maintain separate approval processes. There are also lists of diseases, mostly genetic disorders, that are regarded as rare. As a group they have nothing in common apart from their rarity, but the lists vary strikingly in length; for example, that published by the U.S. National Organization for Rare Disorders contains about 1200 items, whereas the Office of Rare Diseases of the NIH publishes a list of more than 6000, and the EMEA list includes 1127 conditions ranging from Aagenaes syndrome to zygomycosis. (sk)142Science wireDeep Exome Sequences Pin Down Mendelian DisorderIn a proof-of-concept tour de force, a team from the University of Washington in Seattle, Washington was the first to identify the previously unidentified genetic basis for an inherited disorder through whole-exome sequencing.1 The interesting aspect of the study was the design of the approach. They focused sequencing on the coding regions that make up a mere 1% of the whole genome. The execution of the approach to identify genes underlying mendelian disorders, however, required a sophisticated analysis of sequential steps to filter variants and identify which is responsible for the disease phenotype.Four DNA samples from individuals with the rare Miller syndrome were sequenced. Postaxial acrofacial dysostosis, by which the malformation syndrome is also known, manifests itself in anomalies that include severe micrognathia, cleft lip and/or palate, and absent digits among others. It is hoped that this team's finding and the innovative technique used will not only improve diagnosis, but also lead to the faster identification of the genetic signatures of other disorders and conditions and open the door for novel disease targets for gene therapy. (lhv)Industry wireArk Therapeutics, the United Kingdom-based biotech firm with a focus on gene therapies, received a regulatory setback in the approval process for Cerepro, a human adenovirus serotype 5 (hAd5) vector expressing herpes simplex virus thymidine kinase (HSV TK), for the treatment of malignant glioma. In a notice from the European Medicines Agency (EMEA), a rejection from the Committee for Medicinal Products for Human Use (CHMP) stated concerns about the integrity of the Cerepro clinical trial, which in turn brought into doubt the efficacy of the drug relative to existing therapies. Ark Therapeutics has filed an appeal of the decision with the EMEA and is providing additional data about the phase III study in question.Crucell, the Dutch vaccine company, entered a research agreement with the Southwest Foundation for Biomedical Research in San Antonio, Texas. The goal of the collaborative agreement is to test and develop multivalent vaccines against Ebola and Marburg virus in high-level biocontainment animal facilities. The vaccine effort by Crucell is funded by a $30 million dollar grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.Genetix Pharmaceuticals, located in Cambridge, Massachusetts, announced its intent to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration, as well as to expand its European trial on lentiviral gene therapy for the treatment of adrenoleukodystrophy, following the promising human trial results from their French collaborators Drs. Patrick Aubourg and Nathalie Cartier of INSERM.GenVec and Novartis signed a licensing deal in which GenVec received a $5 million dollar up-front payment in anticipation of potential future milestone payments. The collaboration explores novel treatments for hearing loss and balance disorders with the GenVec adenoviral platform. Novartis also purchased approximately $2 million dollars' worth of GenVec common stock.Oxford BioMedica has received a designation for orphan drug status for its gene therapy treatment in development for Stargardt disease, resulting in 10 years of marketing exclusivity and reduced regulatory fees. StarGen's clinical development is announced to start in 2010, in collaboration with Sanofi-Aventis. (lhv)FiguresReferencesRelatedDetails Volume 21Issue 2Feb 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:The Digest/The Wire.Human Gene Therapy.Feb 2010.140-142.http://doi.org/10.1089/hum.2010.2021Published in Volume: 21 Issue 2: February 17, 2010PDF download