Human Gene Therapy Clinical Development最新文献

{"title":"Nonclinical Pharmacology/Toxicology Study of AAV8.TBG.mLDLR and AAV8.TBG.hLDLR in a Mouse Model of Homozygous Familial Hypercholesterolemia.","authors":"Jenny A Greig,&nbsp;Maria P Limberis,&nbsp;Peter Bell,&nbsp;Shu-Jen Chen,&nbsp;Roberto Calcedo,&nbsp;Daniel J Rader,&nbsp;James M Wilson","doi":"10.1089/humc.2017.007","DOIUrl":"https://doi.org/10.1089/humc.2017.007","url":null,"abstract":"<p><p>The homozygous form of familial hypercholesterolemia (HoFH) is an excellent model for developing in vivo gene therapy in humans. The success of orthotropic liver transplantation in correcting the metabolic abnormalities in HoFH suggests that the correction of low-density lipoprotein receptor (LDLR) expression in hepatocytes via gene therapy should be sufficient for therapeutic efficacy. Vectors based on adeno-associated virus serotype 8 (AAV8) have been previously developed for liver-targeted gene therapy of a number of genetic diseases, including HoFH. In preparation for initiating a Phase 1 clinical trial of AAV8-mediated LDLR gene therapy for HoFH, a combined pharmacology/toxicology study was conducted in a mouse model of HoFH. No dose-limiting toxicities were found at or below 6.0 × 10¹³ GC/kg. Therefore, the maximally tolerated dose is greater than the highest dose that was tested. Mild and transient liver pathology was noted at the highest dose. Therefore, the no effect dose was greater than or equal to the middle dose of 7.5 × 10¹² GC/kg. The minimally effective dose was determined to be ≤7.5 × 10¹¹ GC/kg, based on stable reductions in cholesterol that were considered to be clinically significant. This translates to a therapeutic window of ≥80-fold for the treatment of HoFH.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 1","pages":"28-38"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34835241","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":"Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR^+/- Rhesus Macaques.","authors":"Jenny A Greig,&nbsp;Maria P Limberis,&nbsp;Peter Bell,&nbsp;Shu-Jen Chen,&nbsp;Roberto Calcedo,&nbsp;Daniel J Rader,&nbsp;James M Wilson","doi":"10.1089/humc.2017.014","DOIUrl":"https://doi.org/10.1089/humc.2017.014","url":null,"abstract":"<p><p>Vectors based on adeno-associated virus serotype 8 (AAV8) have been evaluated in several clinical trials of gene therapy for hemophilia B with encouraging results. In preparation for a Phase 1 clinical trial of AAV8 gene therapy for the treatment of homozygous familial hypercholesterolemia (HoFH), the safety of the clinical candidate vector, AAV8.TBG.hLDLR, was evaluated in wild-type rhesus macaques and macaques heterozygous for a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene (LDLR^+/-). Intravenous infusion of 1.25 × 10¹³ GC/kg of AAV8.TBG.hLDLR expressing the human version of LDLR was well tolerated and associated with only mild histopathology that was restricted to the liver and sporadic, low-level, and transient elevations in transaminases. Some animals developed T cells to both capsid and the hLDLR transgene, although these adaptive immune responses were most evident at the early time points from peripheral blood and in mononuclear cells derived from the liver. This toxicology study supports the safety of AAV8.TBG.hLDLR for evaluation in HoFH patients, and provides some context for evaluating previously conducted clinical trials of AAV8 in patients with hemophilia.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 1","pages":"39-50"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34835245","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":"Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice.","authors":"Nicola Carriglio,&nbsp;Jan Klapwijk,&nbsp;Raisa Jofra Hernandez,&nbsp;Michela Vezzoli,&nbsp;Franck Chanut,&nbsp;Rhiannon Lowe,&nbsp;Elena Draghici,&nbsp;Melanie Nord,&nbsp;Paola Albertini,&nbsp;Patrizia Cristofori,&nbsp;Jane Richards,&nbsp;Hazel Staton,&nbsp;Jonathan Appleby,&nbsp;Alessandro Aiuti,&nbsp;Aisha V Sauer","doi":"10.1089/humc.2016.191","DOIUrl":"https://doi.org/10.1089/humc.2016.191","url":null,"abstract":"<p><p>GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte antigen-matched related donor is available.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 1","pages":"17-27"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2016.191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34835243","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":"Jurassic Park, Gene Therapy, and Neuroscience: An Interview with Feng Zhang, PhD.","authors":"James M Wilson","doi":"10.1089/humc.2017.29022.int","DOIUrl":"https://doi.org/10.1089/humc.2017.29022.int","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 1","pages":"4-6"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.29022.int","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34785904","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":"Gene Therapy Briefs.","authors":"Alex Philippidis","doi":"10.1089/humc.2017.29023.bfs","DOIUrl":"https://doi.org/10.1089/humc.2017.29023.bfs","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.29023.bfs","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34835242","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":"Differential prevalence of antibodies against adeno-associated virus in healthy children and patients with mucopolysaccharidosis III: perspective for AAV-mediated gene therapy.","authors":"H. Fu, Aaron S. Meadows, R. Pineda, K. Kunkler, K. Truxal, K. McBride, K. Flanigan, D. Mccarty","doi":"10.1089/hum.2017.109","DOIUrl":"https://doi.org/10.1089/hum.2017.109","url":null,"abstract":"Recombinant AAV vectors are promising gene therapy tools. However, pre-existing antibodies (Abs) to many useful AAV serotypes pose a critical challenge for the translation of gene therapies. As part of AAV gene therapy program for treating MPS III patients, we investigated the seroprevalence profiles of AAV1-9 and rh74 in MPS IIIA/IIIB patients and in healthy children. Using ELISA for αAAV-IgG, we observed significantly higher sero-prevalence for AAV1 and AAVrh74 in 2-7y-old MPS III patients than in healthy controls. Seroprevalence for the majority of tested AAV serotypes appear to peak before age 8y in MPS III subjects, with the exception of increases in αAAV8 and αAAV9 Abs in 8-19y-old MPS IIIA patients. In contrast, we observed significant increases in seroprevalence for virtually all tested AAV serotypes in 8-15y-old healthy children compared to 2-7y-olds. Co-prevalence and Ab level correlation results followed the previously established divergence-based clade positions of AAV1-9. Interestingly, the individuals positive for αAAVrh74-Abs showed the lowest co-prevalence with Abs for AAV1-9 (22-40%), however, all or nearly all (77-100%) of subjects that were seropositive for any of serotypes 1-9, were also positive for αAAVrh74-IgG. Notably, the majority (78%) of αAAV seropositive individuals were also Ab-positive for 1-5 of the tested AAV serotypes, mostly with low levels of αAAV-Abs (1:50-100), while a minority (22%) were seropositive for ≥6 AAV serotypes, mostly with high levels of αAAV-IgG for multiple serotypes. In general, the highest IgG levels were reactive to AAV2, AAV3, and AAVrh74. The data illustrate the complex seroprevalence profiles of AAV1-9 and rh74 in MPS patients and healthy children, indicating the potential association of AAV seroprevalence with age and disease conditions. The broad co-prevalence of Abs for different AAV serotypes reinforces the challenge of pre-existing αAAV-Abs for translating AAV gene therapy to clinical applications, regardless of the vector serotype.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91064700","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":"Rationale and Design of a Phase I Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.","authors":"A. M. Waters, J. Johnston, A. Reddy, J. Fiveash, A. Madan-Swain, K. Kachurak, A. Bag, G. Gillespie, J. Markert, G. Friedman","doi":"10.1089/hum.2017.002","DOIUrl":"https://doi.org/10.1089/hum.2017.002","url":null,"abstract":"Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy; and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase I trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75562657","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":"Correction to: Hum Gene Ther Clin Devel 2016;27(4):123-126.","authors":"","doi":"10.1089/humc.2016.29020.bfs.correx","DOIUrl":"https://doi.org/10.1089/humc.2016.29020.bfs.correx","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"11 1","pages":"51"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78400672","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":"Transfer of Therapeutic Genes into Fetal Rhesus Monkeys Using Recombinant Adeno-Associated Type I Viral Vectors.","authors":"T. Conlon, C. Mah, C. A. Pacak, Mary B Rucker Henninger, Kirsten E. Erger, Marda L. Jorgensen, C. I. Lee, A. Tarantal, B. Byrne","doi":"10.1089/HUMC.2016.119","DOIUrl":"https://doi.org/10.1089/HUMC.2016.119","url":null,"abstract":"Neuromuscular disorders such as Pompe disease (glycogen storage disease, type II), result in early and potentially irreversible cellular damage with a very limited opportunity for intervention in the newborn period. Pompe disease is due to deficiency in acid α-glucosidase (GAA) leading to lysosomal accumulation of glycogen in all cell types, abnormal myofibrillogenesis, respiratory insufficiency, neurological deficits, and reduced contractile function in striated muscle. Previous studies have shown that fetal delivery of recombinant adeno-associated virus (rAAV) encoding GAA to the peritoneal cavity of Gaa-/- mice resulted in high-level transduction of the diaphragm. While progression of other genetic disorders may occur later in life, the potential of fetal gene delivery to avoid the onset of irreversible damage suggests it is an attractive option for many inherited diseases. In this study, rhesus monkey fetuses were administered 4.5 × 1012 particles of rAAV type 1 expressing human GAA (rAAV1-CMV-hGAA), human α-1-antitrypsin (rAAV1-CBA-hAAT), or human mini-dystrophin (rAAV1-CMV-miniDMD) in the late first trimester using an established intraperitoneal ultrasound-guided approach. Fetuses were monitored sonographically and newborns delivered at term for postnatal studies. All animals remained healthy during the study period (growth, hematology, and clinical chemistry), with no evidence of adverse effects. Tissues were collected at a postnatal age of 3 months (∼7 months post-fetal gene transfer) for immunohistochemistry (IHC) and quantitative PCR. Both the diaphragm and peritoneum from vector-treated animals were strongly positive for expression of human GAA, AAT, or dystrophin by IHC, similar to findings when reporter genes were used. Protein expression in the diaphragm and peritoneum correlated with high vector copy numbers detected by real-time PCR. Other anatomical areas were negative, although the liver showed minimal evidence of human GAA, AAT, and DMD, vector genomes. In summary, delivery of rAAV vectors provided stable transduction of the muscular component of the diaphragm without any evidence of adverse effects.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"1 1","pages":"152-159"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72572846","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 Study: Intraventricular Injection of a Modified Oncolytic Measles Virus into Measles-Immune, hCD46-Transgenic, IFNαRko Mice.","authors":"Sangeet Lal,&nbsp;Kah-Whye Peng,&nbsp;Michael B Steele,&nbsp;Nathan Jenks,&nbsp;Hong Ma,&nbsp;Gary Kohanbash,&nbsp;Joanna J Phillips,&nbsp;Corey Raffel","doi":"10.1089/humc.2016.062","DOIUrl":"https://doi.org/10.1089/humc.2016.062","url":null,"abstract":"<p><p>The modified Edmonston vaccine strain of measles virus (MV) has shown potent oncolytic efficacy against various tumor types and is being investigated in clinical trials. Our laboratory showed that MV effectively kills medulloblastoma tumor cells in both localized disease and when tumor cells are disseminated through cerebrospinal fluid (CSF). Although the safety of repeated intracerebral injection of modified MV in rhesus macaques has been established, the safety of administering MV into CSF has not been adequately investigated. In this study, we assessed the safety of MV-NIS (MV modified to express the human sodium iodide symporter protein) injected into the CSF of measles-immunized and measles virus-susceptible transgenic (CD46, IFNαRko) mice. Treated animals were administered a single intraventricular injection of 1 × 10⁵ or 1 × 10⁶ TCID₅₀ (50% tissue culture infective dose) of MV-NIS. Detailed clinical observation was performed over a 90-day period. Clinically, we did not observe any measles-related toxic effects or behavioral abnormality in animals of any treated cohort. The complete blood count and blood chemistry analysis results were found to be within normal range for all the cohorts. Histologic examination of brains and spinal cords revealed inflammatory changes, mostly related to the needle track; these resolved by day 21 postinjection. To assess viral biodistribution, quantitative RT-PCR to detect the measles virus N-protein was performed on blood and brain samples. Viral RNA was not detectable in the blood as soon as 2 days after injection, and virus cleared from the brain by 45 days postadministration in all treatment cohorts. In conclusion, our data suggest that a single injection of modified MV into the CSF is safe and can be used in future therapeutic applications.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"27 4","pages":"145-151"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2016.062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34727997","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}