Human Gene Therapy Clinical Development最新文献

Background: Cell and gene therapy products belong to a diverse class of biopharmaceuticals known as advanced therapy medicinal products. Cell and gene therapy products are used for the treatment and prevention of diseases that until recently were only managed chronically. The objective of this study was to examine the characteristics of market authorizations, discontinuations, and prices of cellular and gene therapy products worldwide. Data and Methods: We conducted an electronic search of authorized cell, tissue-engineered, and gene therapy products from the databases of the main drug regulatory agencies. The analysis excluded hematopoietic progenitor cell cord blood products authorized by the U.S. Food and Drug Administration. Price information was derived from the Red Book (Truven Health Analytics) for the United States, health technology assessment agencies for Europe, and other public sector sources and company news for other countries. We also searched the scientific literature for authorizations, discontinuations, and price information using MEDLINE/PubMed, Cochrane Library, Google Scholar, and EMBASE databases. All cost data were converted to U.S. dollars. Descriptive analysis was conducted in this study. Results: There were 52 different cell, tissue engineering and gene therapy products with 69 market authorizations in the world as of December 31, 2018. The products included 18 (34%) cell therapies, 23 (43.4%) tissue engineered products, and 12 (22.6%) gene therapies. There were 21 (30.4% of all authorizations) cell therapy, 26 (37.7%) tissue-engineered, and 22 (31.9%) gene therapy market authorizations. The EMA withdrew the authorization for two tissue engineering products, one cell therapy and one gene therapy, and New Zealand lapsed approval of one cell therapy. Most products were first authorized after 2010, including 10 (83.3%) gene therapies, 13 (72.2%) cell therapies, and 13 (56.5%) tissue-engineered products. The treatment price for four allogenic cell therapies varied from $2,150 in India to $200,000 in Canada. The treatment price for three autologous cell therapies ranged from $61,500 in the United Kingdom to a listed price of $169,206 in the United States. Tissue-engineered treatment prices varied from $400 in South Korea to $123,154 in Japan. Gene therapy treatment prices ranged from $5,501 for tonogenchoncel-L in South Korea to $1,398,321 for alipogene tiparvovec in Germany. Conclusions: A significant number of new cell, tissue, and gene therapies have been approved in the past decade. Most products were conditionally authorized and targeted rare cancers, genetic diseases, and other debilitating diseases. However, there are also products approved for cosmetic reasons. Cell, tissue, and gene therapies are among the most expensive therapies available. Healthcare systems are not prepared to assume the cost of future therapies for a myriad of rare diseases and common

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor with high morbidity and mortality across the world. Recent findings have suggested that long noncoding (lnc)RNA HOXA-AS3 plays an important role in tumorigenesis and metastasis in a variety of cancers. However, the role of lncRNA HOXA-AS3 in the initiation and progression of HCC remains largely unclear. In the present study, HOXA-AS3 was highly expressed in HCC tumor tissues and cell lines. High HOXA-AS3 expression was correlated with low survival of HCC patients. Loss-of-function experiments showed that knockdown of HOXA-AS3 inhibited cell proliferation, migration, invasion, the epithelial-mesenchymal transition (EMT) process, and the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) signaling pathway in HCC. Molecular mechanism exploration uncovered that HOXA-AS3 could directly interact with and negatively regulate miR-29c. BMP1 is a downstream target gene of miR-29c, and HOXA-AS3 could regulate BMP1 expression by targeting miR-29c. miR-29c negatively regulated and BMP1 promoted the progression of HCC. Rescue experiments revealed that miR-29c inhibitor could partially counteract the impact induced by HOXA-AS3 knockdown in HCC. Taken together, our study is the first to show the interaction of HOXA-AS3 with miR-29c in facilitating cell proliferation, metastasis, EMT process, and MEK/ERK signaling pathway in HCC.

General safety and toxicology assessments supporting in vivo lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort (n = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl₄)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (10⁹ TU/mouse) or in combination with DEN/CCl₄ presented clinically similar to control animals, with only slight reductions in total body weight gains over the study period (3.2- to 3.7-fold vs. 4.2-fold). There were no indications of toxicity attributed to administration of LV-FAH alone over the duration of this study. The known hepatotoxic combination of DEN/CCl₄ induced fibrotic liver injury, and co-administration with LV-FAH was associated with exaggeration of some findings such as an increased liver:body weight ratio and progression to focal hepatocyte necrosis in some animals. Hepatocellular degeneration/regeneration was present in DEN/CCl₄-dosed animals regardless of LV-FAH as evaluated by Ki-67 immunohistochemistry and circulating alpha fetoprotein levels, but there were no tumors identified in any tissue in any dose group. These data demonstrate the inherent safety of LV-FAH and support broader clinical development of lentiviral vectors for in vivo administration.

The purpose of this study was to examine the toxicity and side effects of a recombinant adeno-associated virus 8 (AAV8) vector, aimed to treat cyclic nucleotide gated channel alpha 3 (CNGA3)-linked achromatopsia, after a single subretinal administration in cynomolgus macaques. Animals were followed in two studies: a 13-week study with 22 animals and a 28-day study with 12 animals. Both groups were divided into subgroups receiving either vehicle only, a low (1 × 10¹¹ vector genomes (vg)), or a high dose (1 × 10¹² vg) of rAAV.hCNGA3. In the 13-week study, an extra group received single high-dose intravitreal injections. Here we present the group results of the histological examinations carried out after necropsy from the 28-day study, the retinal functional (electroretinography) in the 13-week study, and clinical observations from both studies. Treatment-related adverse effects were not found, and parameter changes were mostly related to the surgical procedure. The treatment of achromatopsia with rAAV.hCNGA3 is therefore deemed safe to apply to humans.

microRNAs (miRNAs) have been widely recognized as crucial regulators for tumorigenesis. However, the role of miR-632 in hepatocellular carcinoma (HCC) remains largely unknown. miR-632 expression in HCC cell lines was determined by quantitative real-time polymerase chain reaction. The role of miR-632 expression on overall survival of HCC patients was examined on the Kaplan-Meier plotter Web site. The dual luciferase reporter method was performed to investigate whether myc target 1 (MYCT1) was a target of miR-632. Cell counting kit-8 assay, colony formation assay, and Transwell invasion assay were performed to examine cell proliferation, colony formation, and cell invasion of HCC cells. The results showed miR-632 expression was elevated in HCC cell lines compared to normal cell lines. Loss-of-function experiments demonstrated that miR-632 downregulation was able to inhibit HCC cell proliferation, colony formation, and cell invasion. Moreover, miR-632 could negatively regulate the expression of MYCT1 in HCC cells. Importantly, the study showed miR-632 and MYCT1 were negatively correlated by analyzing the public data sets obtained from the Gene Expression Omnibus. Knockdown of MYCT1 by small interfering RNA partially reversed the effects of miR-632 on HCC cell events. The present study suggests that miR-632 regulates growth and invasion of HCC cells through targeting MYCT1.

Glioblastomas (GBMs) are the most prevalent brain tumor and exhibit poor prognosis. Radiotherapy is an important strategy for GBMs patients; however, this care remains palliative because of GBMs' radioresistance. Glioma stem cells (GSCs), as a subpopulation residing at the apex of the hierarchy, have been believed to be a pivotal population in radioresistance and recurrence of GBMs. To know the key genes involved in radioresistance of GSCs, the gene expression profiles of GSE54660 and GSE60921 were downloaded from Gene Expression Omnibus for genetic and transcriptomic analysis to identify the potential biomarker genes differentially expressed between GSCs and GBMs. These candidate genes were then filtered by the GSCs gene profile responding to radiation and the radioresistant biomarker genes including DNAJC9, GINS2, STAT1, CHAC2, MT1M, and ZNF226 were screened. The differentially expressed genes in GSCs post-irradiation were submitted to Gene Ontology (GO) for further enrichment analysis and protein-protein interaction (PPI) network analysis. A significant module correlated with GINS2 was finally chosen and a series of genes participating in DNA metabolism were identified. In conclusion, this study propounds a set of novel genes that are differentially expressed in the radioresistant subpopulation within GBMs and could serve as promising therapeutic targets.

Editor's note: Sir Patrick Vallance is Government Chief Scientific Adviser in the United Kingdom. Here he discusses his path from academia to industry to government, and he reflects on the crucial early conversations that were instrumental in positioning gene therapy research for successful clinical development.

Malignant melanoma is an aggressive tumor with high fatality rates and poor prognosis, mainly due to the lack of efficient treatment methods. The present study investigated the potential antitumor effects of recombinant adenovirus p53 (rAd-p53) on human malignant melanoma. The optimal viral titer on a human malignant melanoma (A-375) cell line was determined for the rAd-p53 treatment. The invasive abilities, apoptosis, variations in the cell cycle, and molecular expression levels of A-375 cells were detected after infection by rAd-p53. A tumor growth curve and hematoxylin and eosin staining were carried out for experiments in nude mice. Twenty-one patients with malignant melanoma were evaluated, including 12 cases without gene therapy and nine cases with rAd-p53 gene therapy. The overall survival rate and the median survival time were analyzed between the two groups of patients. When the multiplicity of infection was 100, the cells showed the best transfection efficiency. The invasive ability, apoptosis, cycle changes of the cells, and the expression of the p53, p21, and Bax genes and proteins were significantly changed in the experimental group. In nude mice, the tumor growth curve and the tumor size in the experimental group were significantly smaller than those of the control group. Hematoxylin and eosin staining revealed tumor metastasis in the blank group and the control group but not in the experimental group. Between the two groups of patients, the median survival of the gene therapy group (38 months) was greater than that of the group without gene therapy (27 months). In this study, high expression of the p53 gene could regulate the gene expression and reduce the invasive and metastatic abilities of the tumor cells. Furthermore, rAd-p53 effectively improved the survival of patients with malignant melanoma. Therefore, rAd-p53 may be a potential treatment method for human malignant melanoma.

Gastric cancer (GC) is the second primary cause of cancer-associated mortality around the world. Long noncoding RNAs (lncRNAs) are critical modulators of multiple cellular processes, and their abnormal expression and/or function are related to a variety of diseases, including cancer. Various lncRNAs have been shown to exert a functional role in GC, but more still remain to be identified, since the therapies for GC patients are limited. Here we discover LINC02465, a novel recognized lncRNA, is upregulated and correlated with tumor size, tumor stage, lymph node metastasis, and differentiation in gastric cancer. In addition, we found that high LINC02465 level in GC patients is closely related to poor prognosis. Moreover, our findings reveal that LINC02465 silence suppresses cell proliferation and migration, invasion, and epithelial-mesenchymal transition in vitro. Conversely, LINC02465 overexpression displays a completely opposite way. Meanwhile, LINC02465 inhibition also limits tumor growth in vivo. Mechanistically, LINC02465 inhibition inactivates PI3K/AKT signaling pathway, and the activation of this pathway by 740Y-P reverses the inhibition effect of LINC02465 suppression on biological behaviors of GC cells. Taken together, LINC02465 is an oncogenic lncRNA that facilitates the tumorigenesis and progression of GC via PI3K/AKT pathway, demonstrating a novel effective therapeutic target and prognostic biomarker for GC patients.