Human Gene Therapy Clinical Development最新文献

{"title":"Standing on the Shoulders of Stem Cell Gene Therapists: History, Hyperbole, and Hope for the Future","authors":"GardnerJason","doi":"10.1089/HUMC.2016.127","DOIUrl":"https://doi.org/10.1089/HUMC.2016.127","url":null,"abstract":"A new type of medicine approved in Europe at the end of May represents the culmination of the successful convergence of two fields of science: stem cell transplantation and gene therapy. Strimvelis, a patient-specific gene-modified stem cell medicine for ADA-SCID (adenosine deaminase deficiency leading to severe combined immunodeficiency; a fatal immunometabolic disorder similar to the bubble-boy disease), was developed by scientists at the San Raffaele Telethon Institute for Gene Therapy (TIGET) in Milan, Italy, which then later partnered with GlaxoSmithKline (GSK, Brentford, UK). The journey took more than 25 years of dedicated work by many groups and involved a pivotal trial with 12 children and their brave families. I was fortunate to be involved on the GSK side of the TIGET alliance from 2010 to 2015, building on my previous experiences with gene-modified stem cells during a postdoctoral fellowship in the mid-1990s and at Chiron, which had acquired Viagene, an early gene therapy biotech firm. I thoug...","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90910230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interview with Katherine A. High, MD.","authors":"J. M. Wilson","doi":"10.1089/HUMC.2016.29021.INT","DOIUrl":"https://doi.org/10.1089/HUMC.2016.29021.INT","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"5 1","pages":"127-131"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74650529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"User-Friendly Technology the Key to Gene-Editing's Bloom: Market for Gene-Editing Tools Estimated at $608m and Growing as New Applications Are Found.","authors":"CarlsonBruce","doi":"10.1089/HUMC.2016.29019.PER","DOIUrl":"https://doi.org/10.1089/HUMC.2016.29019.PER","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"1 1","pages":"137-139"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88658492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investor Outlook: Solving Gene Therapy Pricing…with a Cures Voucher?","authors":"SchimmerJoshua, BreazzanoSteven","doi":"10.1089/HUMC.2016.29018.IND","DOIUrl":"https://doi.org/10.1089/HUMC.2016.29018.IND","url":null,"abstract":"Gene therapy reimbursement continues to be an intense topic of discussion in the field given the unique and durable benefits from a single administration and generally small patient populations against a reimbursement framework that is not optimized for such “cures” or long-lived benefits. As more gene therapy programs enter the market and late-stage development, it is increasingly important for the field to define a reimbursement model that works for all stakeholders in order to encourage the next wave of innovation. To add to the discussion around new payment models and potential solutions, we propose a flexible voucher system that takes advantage of existing infrastructure, precedent, and regulatory frameworks.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"18 1","pages":"132-136"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86010921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investor Outlook: Gene Therapy Picking up Steam; At a Crossroads.","authors":"SchimmerJoshua, BreazzanoSteven","doi":"10.1089/HUMC.2016.29017.IND","DOIUrl":"https://doi.org/10.1089/HUMC.2016.29017.IND","url":null,"abstract":"The gene therapy field continues to pick up steam with recent successes in a number of different therapeutic indications that highlight the potential for the platform. As the field continues to make progress, a growing data set of long-term safety and efficacy data will continue to define gene therapy's role, determining ultimately how widely it may be used beyond rare, serious diseases with high unmet needs. New technologies often take unanticipated twists and turns as patient exposure accumulates, and gene therapy may be no exception. That said, with many diseases that have no other treatment options beyond gene therapy and that present considerable morbidity and mortality, the field appears poised to withstand some minor and even major bumps in the road should they emerge.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"78 1","pages":"87-92"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84956800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translation and Reimbursement: The Twin Challenges for Cell and Gene Therapies Reflections of an Ex-Regulator.","authors":"Gopalan Narayanan","doi":"10.1089/humc.2016.093","DOIUrl":"https://doi.org/10.1089/humc.2016.093","url":null,"abstract":"NOT A DAY GOES BY without news related to a scientific advance involving cell and/or gene therapies (also referred to as advanced therapy medicinal products, or ATMPs, in the European Union) for various poorly met medical needs. Per Clinicaltrials.gov (16 August, 2016), there are more than 9,700 studies that involve either gene therapy or stem cell therapy. However, there are two aspects of development of these products that could pose significant challenges to make them successful therapeutic reality. The first potentially challenging aspect is early translation to clinical studies. Traditional approaches to medicine development for early phase human studies that have evolved from small molecule chemicals are usually not very helpful for many reasons. Healthy volunteer studies may be difficult to carry out for ethical and scientific reasons. For example, it might not be feasible to administer the test product if the intended clinical use involves direct delivery into an organ. When planning studies in patients, a control (e.g., placebo) arm may or may not be acceptable for similar reasons. Another significant challenge is dose-finding studies, which are usually only possible in patients. It is not generally ideal to give suboptimal doses to patients, as many of these products are for single administration only. Further, factors such as immunogenicity could make it impossible for those patients to receive the therapeutic dose at a later date. Many such therapies are being developed for rare diseases such as inborn errors of metabolism. As there are limited numbers of patients who will be eligible and willing to volunteer for a clinical trial, this puts additional emphasis on getting it right for the design and strategy of clinical development as a whole. While regulators are sympathetic and realistic about these factors, the combination of a complex therapy such as geneor cell-based therapies and a rare disease can make evidence generation that is robust and reproducible for regulatory approval difficult. The second significant hurdle for successful commercialization of these products is the issue of reimbursement. The complexity of manufacturing these products requiring highly skilled professionals and the regulatory requirement for strict quality control can have a significant impact on the cost of manufacturing. This will inevitably need to be recovered through appropriate pricing and reimbursement. Establishing such a complex facility for a rare disease indication can add to the pressure, as it will have additional impact on pricing. Another important factor to consider is transport and storage. Some of the autologous products may need to be prepared and administered close to the manufacturing site, which will require patients (and parents in cases of children needing the product) to travel to receive the product and stay close to the site for a certain period following administration, further increasing the expenses thus incurred. The challe","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"27 3","pages":"93-5"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2016.093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34326992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing Transgene Configuration and Protein Fusions to Maximize Dopamine Production for the Gene Therapy of Parkinson's Disease.","authors":"Hannah J Stewart,&nbsp;G Scott Ralph,&nbsp;Liang Fong-Wong,&nbsp;Iain Strickland,&nbsp;Laura McCloskey,&nbsp;Lucy Barnes,&nbsp;Ian Blount,&nbsp;Owen Wells,&nbsp;Christelle J M Truran,&nbsp;Alan J Kingsman,&nbsp;Stéphane Palfi,&nbsp;Kyriacos A Mitrophanous","doi":"10.1089/humc.2016.056","DOIUrl":"https://doi.org/10.1089/humc.2016.056","url":null,"abstract":"<p><p>Pharmacological dopamine replacement therapies provide the most well-established treatments for Parkinson's disease (PD). However, these long-term treatments can lead to motor complications and off-target effects. ProSavin(®), a lentiviral vector (LV)-based gene therapy approach aimed at restoring local and continuous dopamine production, through delivery of three enzymes in the dopamine biosynthesis pathway, was demonstrated to be safe and well-tolerated in a phase I/II clinical study of patients with advanced PD. Although improvements in motor behaviour were observed, the data indicated that higher levels of dopamine replacement might be required to maximize benefit. We attempted to increase production of dopamine, and its precursor L-Dopa in LV-transduced cells, by optimizing the gene order in the ProSavin expression cassette, and by creating fusions of two or three of the transgenes, using linker sequences. In vitro analysis showed that several gene arrangements provided significantly increased dopamine and/or L-Dopa production compared with ProSavin, and that LV titers and transgene expression were not affected by introducing gene fusions. One vector, equine infectious anemia virus (EIAV)-TCiA, was selected for further characterization and showed significant improvements in dopamine and L-Dopa production compared with ProSavin, in human neuronal cells. Further characterization of EIAV-TCiA demonstrated expression of all three dopamine enzymes in vivo and faithful delivery and integration of the expected gene expression cassette within the genome of target cells, as assessed by Northern and Southern blotting. In conclusion, we have developed a novel LV vector with an increased capacity for L-Dopa and dopamine production compared with the current ProSavin vector. Clinical evaluation of this vector will be performed to assess the benefits in patients with PD.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"27 3","pages":"100-10"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2016.056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34713400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luigi Naldini on His Lifelong Involvement with the Development of Gene Therapy.","authors":"James M Wilson","doi":"10.1089/humc.2016.29016.int","DOIUrl":"https://doi.org/10.1089/humc.2016.29016.int","url":null,"abstract":"I joined the Salk to venture into the growing field of gene therapy. At that time I remember reading an editorial or interview by Harold Varmus about the problems of gene therapy, which were vectors, vectors, and vectors. This call to arms by Harold regarding vectors resonated with me and provided me with direction as to where to take my career. The key aspect was not enough efficiency. The Salk was a unique place for addressing that because of the combined expertise available. I joined the laboratory of Inder Verma, who had a lot of experience in developing gene therapies. Upstairs was a virology laboratory, where Didier Trono was working on HIV and discovering its unique ability to enter into the nucleus of infected non-dividing cells, a difference from other retroviruses. We applied the concept of exploiting HIV—and its unique capacity to infect cells and gain access to their nuclei—to make a more efficient vector. The other aspect of our research, once we had the vector built, was to prove that it was indeed more efficient. One important question was whether this vector would be able to transduce a non-dividing cell, which was the property we were trying to capture from HIV. The best model available at that Luigi Naldini, MD, PhD Director San Raffaele Telethon Institute for Gene Therapy Professor Cell and Tissue Biology and Gene Therapy School of Medicine Vita-Salute San Raffaele University Milan, Italy","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"27 3","pages":"83-6"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2016.29016.int","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34332091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Studies in Tumor and Non-Tumor-Bearing Mice in Support of Clinical Trials Using Oncolytic VSV-IFNβ-NIS.","authors":"Lianwen Zhang,&nbsp;Michael B Steele,&nbsp;Nathan Jenks,&nbsp;Jacquelyn Grell,&nbsp;Lukkana Suksanpaisan,&nbsp;Shruthi Naik,&nbsp;Mark J Federspiel,&nbsp;Martha Q Lacy,&nbsp;Stephen J Russell,&nbsp;Kah-Whye Peng","doi":"10.1089/humc.2016.061","DOIUrl":"https://doi.org/10.1089/humc.2016.061","url":null,"abstract":"<p><p>Oncolytic VSV-IFNβ-NIS is selectively destructive to tumors. Here, we present the IND enabling preclinical rodent studies in support of clinical testing of vesicular stomatitis virus (VSV) as a systemic therapy. Efficacy studies showed dose-dependent tumor regression in C57BL/KaLwRij mice bearing syngeneic 5TGM1 plasmacytomas after systemic VSV administration. In contrast, the virus was effective at all doses tested against human KAS6/1 xenografts in SCID mice. Intravenous administration of VSV-mIFNβ-NIS is well tolerated in C57BL/6 mice up to 5 × 10(10) TCID50 (50% tissue culture infective dose)/kg with no neurovirulence, no cytokine storm, and no abnormalities in tissues. Dose-limiting toxicities included elevated transaminases, thrombocytopenia, and lymphopenia. Inactivated viral particles did not cause hepatic toxicity. Intravenously administered VSV was preferentially sequestered by macrophages in the spleen and liver. Quantitative RT-PCR analysis for total viral RNA on days 2, 7, 21, and 58 showed highest VSV RNA in day 2 samples; highest in spleen, liver, lung, lymph node, kidney, gonad, and bone marrow. No infectious virus was recovered from tissues at any time point. The no observable adverse event level and maximum tolerated dose of VSV-mIFNβ-NIS in C57BL/6 mice are 10(10) TCID50/kg and 5 × 10(10) TCID50/kg, respectively. Clinical translation of VSV-IFNβ-NIS is underway in companion dogs with cancer and in human patients with relapsed hematological malignancies and endometrial cancer.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"27 3","pages":"111-22"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2016.061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34375961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Standing on the shoulders of stem cell gene therapists: history, hyperbole and hope for the future.","authors":"J. Gardner","doi":"10.1089/hum.2016.127","DOIUrl":"https://doi.org/10.1089/hum.2016.127","url":null,"abstract":"A new type of medicine was approved in Europe at the end of May that culminated from the successful convergence of two fields of science: stem cell transplantation and gene therapy. Strimvelis, a patient-specific gene-modified stem cell medicine for ADA-SCID (a fatal immunometabolic disorder similar to the bubble-boy disease), was developed by scientists at the San Raffaele Telethon Institute for Gene Therapy (TIGET) in Milan, then later partnered with GSK. The journey took over 25 years of dedicated work from many groups and involved a pivotal trial with 12 children and their brave families. I was fortunate to be involved on the GSK side of the TIGET alliance from 2010-2015, building upon my previous experiences in gene-modified stem cells during a post-doctoral fellowship in the mid-1990s and at Chiron, which had acquired Viagene, an early gene therapy biotech. I thought it was timely to pick out a couple of observations from the development of Strimvelis to see how these might apply not only for the future of stem cell gene therapy but also be the shoulders for the adjacent CAR-T and gene editing technologies to stand on.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79363929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}