Human Gene Therapy Clinical Development最新文献

{"title":"A Multicenter, Double-Blind, Phase III Clinical Trial to Evaluate the Efficacy and Safety of a Cell and Gene Therapy in Knee Osteoarthritis Patients.","authors":"Myung-Ku Kim,&nbsp;Chul-Won Ha,&nbsp;Yong In,&nbsp;Sung-Do Cho,&nbsp;Eui-Sung Choi,&nbsp;Jeong-Ku Ha,&nbsp;Ju-Hong Lee,&nbsp;Jae-Doo Yoo,&nbsp;Seong-Il Bin,&nbsp;Choong-Hyeok Choi,&nbsp;Hee-Soo Kyung,&nbsp;Myung-Chul Lee","doi":"10.1089/humc.2017.249","DOIUrl":"https://doi.org/10.1089/humc.2017.249","url":null,"abstract":"<p><p>The aim of this study was to test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1) retrovirally transduced to overexpress transforming growth factor-β1. A total of 163 Kellgren-Lawrence grade 3 patients with knee osteoarthritis were randomly assigned to receive intra-articular TG-C or placebo. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks. Secondary efficacy measures included IKDC and VAS at 26 and 39 weeks; pain, stiffness, and physical function by the Western Ontario and McMaster Universities Arthritis Index (WOMAC); and pain, symptoms, daily activities, function in sports and recreation, and quality of life by the Knee Injury and Osteoarthritis Outcome Score (KOOS), X-ray, magnetic resonance imaging, and soluble urine and blood biomarkers. TG-C was associated with statistically significant improvement over placebo in the total IKDC score and individual categories, and in the VAS score at 26, 39, and 52 weeks. WOMAC and KOOS scores also improved with TG-C over placebo. Patients treated with TG-C showed trends directed toward thicker cartilage and slower growing rates of subchondral bone surface area in the medial tibia, lateral tibia, lateral patella, and lateral patella femoral regions, although these were not statistically significant (p > 0.05). Serum C-terminal telopeptide of type I collagen (CTX-I) and urine CTX-II levels were lower over 1 year in TG-C than placebo-treated patients, with CTX-I level reaching statistical significance. These tendencies supported TG-C as holding great potential as a disease-modifying osteoarthritis drug. The most frequent adverse events in the TG-C group were peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection site pain (5%). TG-C was associated with statistically significant improvements in function and pain in patients with knee osteoarthritis. The unexpected adverse events were not observed.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"29 1","pages":"48-59"},"PeriodicalIF":0.0,"publicationDate":"2018-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35999736","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.2018.29033.bfs","DOIUrl":"https://doi.org/10.1089/humc.2018.29033.bfs","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"29 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2018-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2018.29033.bfs","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35999735","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":"Low Seroprevalence of Neutralizing Antibodies Targeting Two Clade F AAV in Humans.","authors":"J. Ellsworth, M. Ocallaghan, Hillard L. Rubin, A. Seymour","doi":"10.1089/hum.2017.239","DOIUrl":"https://doi.org/10.1089/hum.2017.239","url":null,"abstract":"To assess the therapeutic utility of AAVHSC15 and AAVHSC17, two recently described Clade F adeno-associated viruses, the seroprevalence of neutralizing antibodies to these AAVs was assessed in a representative human population and compared to that of AAV9. Neutralizing antibody levels were measured in 100 unique human sera of different races (34:33:33, Black:Caucasian:Hispanic) and sex (49% Female, 51% Male) collected within the United States. Fifty-six sera were tested in HuH7 cells and 44 sera were tested in 2V6.11 cells with vectors packaged with either a CMV-promoter upstream of LacZ or a CBA-promoter upstream of Firefly Luciferase, respectively. For AAVHSC15, AAVHSC17, and AAV9, 24/100 (24%), 21/100 (21%), and 17/100 (17%), respectively, of all sera tested were seropositive for neutralizing antibodies using 50% inhibition of cellular transduction at a 1/16 dilution of serum as cut-off for seropositivity. Only six percent of positive sera had titers of 1/150 to 1/340 indicating that the majority of positive sera were of low titer. Significant cross-reactivity of neutralizing antibodies across all three AAV serotypes was observed. These data show that approximately 80% of humans evaluated were seronegative for pre-existing neutralizing antibodies to the AAV serotypes tested, suggesting that the vast majority of human subjects would be amenable to therapeutic intervention with Clade F AAVs.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90156675","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":"A Multicenter, Double-Blind, Phase III Clinical Trial to Evaluate the Efficacy and Safety of a Cell and Gene Therapy in Knee Osteoarthritis Patients.","authors":"M. Kim, C. Ha, Y. In, Sung-Do Cho, Eui-Sung Choi, J. Ha, Ju-Hong Lee, J. Yoo, S. Bin, C. Choi, H. Kyung, M. Lee","doi":"10.1089/hum.2017.249","DOIUrl":"https://doi.org/10.1089/hum.2017.249","url":null,"abstract":"OBJECTIVE To test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1), retrovirally transduced to overexpress TGF-β1. DESIGN We randomly assigned 163 with knee osteoarthritis to receive intra-articular TG-C or placebo in Kellgren-Lawrence grade 3 patients for clinical trial. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks. Secondary efficacy measures included IKDC and VAS at 26 and 39 weeks; pain, stiffness, and physical functions by the Western Ontario and McMaster Universities Arthritis Index (WOMAC); and pain, symptoms, daily activities, functions in sports and recreation, and quality of life by the Knee Injury and Osteoarthritis Outcome Score (KOOS), X ray, MRI, and soluble urine and blood biomarkers. RESULTS TG-C was associated with statistically significant improvement over placebo in the total IKDC score and individual categories, and in the VAS score at 26, 39, and 52 weeks. WOMAC and KOOS scores also improved with TG-C over placebo. Patients treated with TG-C showed trends directed towards thicker cartilage and slower growing rates of subchondral bone surface area in the medial tibia, lateral tibia, lateral patella, and lateral patella femoral regions, although not statistically significant (P > 0.05). Serum CTX-I and urine CTX II levels showed lower over 1 year in TG-C than placebo treated patients with CTX-I level reaching statistical significance. These tendencies supported TG-C as holding a great potential for disease-modifying osteoarthritis drug. The most frequent adverse events in the TG-C group were peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%). CONCLUSIONS TG-C was associated with statistically significant improvements in functions and pain in patients with knee osteoarthritis. The unexpected adverse events were not observed. TRIAL REGISTRATION clinicaltrials.gov NCT02072070 and CRiS: KCT0001112.","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89030441","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":"Carl June Speaks of His Pioneering Efforts That Led to the First Food and Drug Administration-Approved Gene Therapy Product.","authors":"James M Wilson","doi":"10.1089/humc.2017.29029.int","DOIUrl":"https://doi.org/10.1089/humc.2017.29029.int","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 4","pages":"175-177"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.29029.int","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35547566","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 and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs.","authors":"Guo-Jie Ye,&nbsp;András M Komáromy,&nbsp;Caroline Zeiss,&nbsp;Roberto Calcedo,&nbsp;Christine D Harman,&nbsp;Kristin L Koehl,&nbsp;Gabriel A Stewart,&nbsp;Simone Iwabe,&nbsp;Vince A Chiodo,&nbsp;William W Hauswirth,&nbsp;Gustavo D Aguirre,&nbsp;Jeffrey D Chulay","doi":"10.1089/humc.2017.125","DOIUrl":"https://doi.org/10.1089/humc.2017.125","url":null,"abstract":"<p><p>Achromatopsia is an inherited retinal disorder of cone photoreceptors characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. Approximately 50% of cases are caused by mutations in the cone photoreceptor-specific cyclic nucleotide gated channel beta subunit (CNGB3) gene. Studies in CNGB3-mutant dogs showed that subretinal injection of an AAV vector expressing human CNGB3, which has 76% amino acid identity with canine CNGB3, driven by a 2.1 kb human red cone opsin promoter (PR2.1) and packaged in AAV5 capsids (AAV5-PR2.1-hCNGB3) rescued cone photoreceptor function, but at high doses was associated with an inflammatory response (focal chorioretinitis) consistent with immune-mediated toxicity. AAV vectors containing the PR2.1 promoter packaged in AAV5 capsids and expressing either the native canine CNGB3 (AAV5-PR2.1-cCNGB3) or the human CNGB3 (AAV5-PR2.1-hCNGB3) were evaluated at different dose levels in CNGB3-mutant dogs. The vector expressing canine CNGB3 achieved somewhat better rescue of cone function but unexpectedly was associated with a greater degree of retinal toxicity than the vector expressing human CNGB3. Very low-level T-cell immune responses to some AAV or CNGB3 peptides were observed in animals that received the higher vector dose. There was a more than twofold increase in serum neutralizing antibodies to AAV in one of three animals in the low-dose group and in two of three animals in the high-dose group. No serum anti-hCNGB3 antibodies were detected in any animal. The results of this study do not support the hypothesis that the focal chorioretinitis seen with high doses of AAV5-PR2.1-hCNGB3 in the initial studies was due to an immune response to human CNGB3.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 4","pages":"197-207"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35498569","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":"Safety of Intradiaphragmatic Delivery of Adeno-Associated Virus-Mediated Alpha-Glucosidase (rAAV1-CMV-hGAA) Gene Therapy in Children Affected by Pompe Disease.","authors":"Manuela Corti,&nbsp;Cristina Liberati,&nbsp;Barbara K Smith,&nbsp;Lee Ann Lawson,&nbsp;Ibrahim S Tuna,&nbsp;Thomas J Conlon,&nbsp;Kirsten E Coleman,&nbsp;Saleem Islam,&nbsp;Roland W Herzog,&nbsp;David D Fuller,&nbsp;Shelley W Collins,&nbsp;Barry J Byrne","doi":"10.1089/humc.2017.146","DOIUrl":"https://doi.org/10.1089/humc.2017.146","url":null,"abstract":"<p><p>A first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease was conducted. The primary objective of this study was to assess the safety of rAAV1-CMV-hGAA vector delivered to the diaphragm muscle of Pompe disease subjects with ventilatory insufficiency. Safety was assessed by measurement of change in serum chemistries and hematology, urinalysis, and immune response to GAA and AAV, as well as change in level of health. The data demonstrate that the AAV treatment was safe and there were no adverse events related to the study agent. Adverse events related to the study procedure were observed in subjects with lower baseline neuromuscular function. All adverse events were resolved before the end of the study, except for one severe adverse event determined not to be related to either the study agent or the study procedure. In addition, an anti-capsid and anti-transgene antibody response was observed in all subjects who received rAAV1-CMV-hGAA, except for subjects who received concomitant immunomodulation to manage reaction to enzyme replacement therapy, as per their standard of care. This observation is significant for future gene therapy studies and serves to establish a clinically relevant approach to blocking immune responses to both the AAV capsid protein and transgene product.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 4","pages":"208-218"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35271899","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":"The Gene Therapy Resource Program: A Decade of Dedication to Translational Research by the National Heart, Lung, and Blood Institute.","authors":"Terence R Flotte, Eric Daniels, Janet Benson, Jeneé M Bevett-Rose, Kenneth Cornetta, Margaret Diggins, Julie Johnston, Susan Sepelak, Johannes C M van der Loo, James M Wilson, Cheryl L McDonald","doi":"10.1089/humc.2017.170","DOIUrl":"10.1089/humc.2017.170","url":null,"abstract":"<p><p>Over a 10-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice clinical-grade vector cores for recombinant adeno-associated virus and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early-phase clinical trials. In addition, the GTRP has utilized a Steering Committee and a Scientific Review Board to guide overall progress and effectiveness and to evaluate individual proposals. These resources have been deployed to assist 82 investigators with 172 approved service proposals. These efforts have assisted in clinical trial implementation across a wide range of genetic, cardiac, pulmonary, and blood diseases. Program outcomes and potential future directions of the program are discussed.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 4","pages":"178-186"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733658/pdf/humc.2017.170.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35248102","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":"Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy.","authors":"Haiyan Fu,&nbsp;Aaron S Meadows,&nbsp;Ricardo J Pineda,&nbsp;Krista L Kunkler,&nbsp;Kristen V Truxal,&nbsp;Kim L McBride,&nbsp;Kevin M Flanigan,&nbsp;Douglas M McCarty","doi":"10.1089/humc.2017.109","DOIUrl":"https://doi.org/10.1089/humc.2017.109","url":null,"abstract":"<p><p>Recombinant adeno-associated virus (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 mucopolysaccharidosis (MPS) III patients, the seroprevalence profiles of AAV1-9 and rh74 were investigated in MPS IIIA/IIIB patients and in healthy children. Using enzyme-linked immunosorbent assay for αAAV-IgG, significantly higher seroprevalence was observed for AAV1 and AAVrh74 in 2- to 7-year-old MPS III patients than in healthy controls. Seroprevalence for the majority of tested AAV serotypes appears to peak before 8 years of age in MPS III subjects, with the exception of increases in αAAV8 and αAAV9 Abs in 8- to 19-year-old MPS IIIA patients. In contrast, significant increases in seroprevalence were observed for virtually all tested AAV serotypes in 8- to 15-year-old healthy children compared to 2- to 7-year-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 who 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 one to five of the tested AAV serotypes, mostly with low levels of αAAV-Abs (1:50-100), while a minority (22%) were seropositive for six or more 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.</p>","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":" ","pages":"187-196"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39984030","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":"2017 Is the Year We Have Been Waiting For.","authors":"James M Wilson","doi":"10.1089/humc.2017.29030.wil","DOIUrl":"https://doi.org/10.1089/humc.2017.29030.wil","url":null,"abstract":"","PeriodicalId":51315,"journal":{"name":"Human Gene Therapy Clinical Development","volume":"28 4","pages":"165-166"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/humc.2017.29030.wil","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35659333","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}