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In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions.

ABSTRACT: Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy is well tolerated and provides stable long-term expression of FAH in pigs with HT1. Genomic integration displays a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.

SUBMITTER: Nicolas CT

PROVIDER: S-EPMC9411607 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions.

Nicolas Clara T CT VanLith Caitlin J CJ Hickey Raymond D RD Du Zeji Z Hillin Lori G LG Guthman Rebekah M RM Cao William J WJ Haugo Benjamin B Lillegard Annika A Roy Diya D Bhagwate Aditya A O'Brien Daniel D Kocher Jean-Pierre JP Kaiser Robert A RA Russell Stephen J SJ Lillegard Joseph B JB

Nature communications 20220825 1

Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy is well ...[more]

PMID: 36008405

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Project description:Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small- and large-animal models of HT1. This study hypothesized that ex vivo hepatocyte-directed gene editing using CRISPR/Cas9 could be used to correct a mouse model of HT1, in which a single point mutation results in loss of FAH function. To achieve high transduction efficiencies of primary hepatocytes, this study utilized a lentiviral vector (LV) to deliver both the Streptococcus pyogenes Cas9 nuclease and target guide RNA (LV-Cas9) and an adeno-associated virus (AAV) vector to deliver a 1.2 kb homology template (AAV-HT). Cells were isolated from Fah-/- mice and cultured in the presence of LV and AAV vectors. Transduction of cells with LV-Cas9 induced significant indels at the target locus, and correction of the point mutation in Fah-/- cells ex vivo using AAV-HT was completely dependent on LV-Cas9. Next, hepatocytes transduced ex vivo by LV-Cas9 and AAV-HT were transplanted into syngeneic Fah-/- mice that had undergone a two-thirds partial hepatectomy or sham hepatectomy. Mice were cycled on/off the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) to stimulate expansion of corrected cells. All transplanted mice became weight stable off NTBC. However, a significant improvement was observed in weight stability off NTBC in animals that received partial hepatectomy. After 6 months, mice were euthanized, and thorough biochemical and histological examinations were performed. Biochemical markers of liver injury were significantly improved over non-transplanted controls. Histological examination of mice revealed normal tissue architecture, while immunohistochemistry showed robust repopulation of recipient animals with FAH+ cells. In summary, this is the first report of ex vivo hepatocyte-directed gene repair using CRISPR/Cas9 to demonstrate curative therapy in an animal model of liver disease.

Project description:The objectives of this study were to identify the associated factors with cancerous and precancerous lesions of cervix. In Africa, the incidence of uterine cervical neoplasms varies from one region to another, where most women with uterine cervical neoplasms are seen at an advanced stage. For this reason, uterine cervical neoplasms mass screening reduces the incidence and mortality due to this disease, similar to what is being done in Europe. A cross-sectional analytical study was conducted. Socio-demographic characteristics, gynaecological-obstetrical history, risk factors, data from visual inspection with acetic acid and visual inspection with Lugol, colposcopy impressions and results of cytological analysis were performed. A simple and multiple regression were performed to establish a statistically significant difference between certain factors and the presence of precancerous or cancerous lesions of uterine cervical. In this study, of 63 women diagnosed histologically, 43 had precancerous lesions and 20 had cancerous lesions. we found that being older than 35, having the first intercourse before 18, having an antecedent of STI, being a widow and using of tobacco were risk factors associated with precancerous lesions (p = 0.013 with OR = 3.44 (1.22-9.73), p = 0.009 with OR = 4.07 (1.69-13.08), p < 0.001 with OR = 3.80 (1.94-7.47), p < 0.001 with OR = 9.77 (3.87-24.70) and p < 0.001 with OR = 5.47 (2.60-11.52)) respectively. Only being older than 45, being a widow and using tobacco were risk factors associated with cancerous lesions (p = 0.021 with OR = 2.01 (1.58-3.56), p = 0.02 with OR = 2.96 (2.10-3.87), p = 0.041 with OR = 1.98 (1.46-2.44)) respectively. Among participants diagnosed with uterine cervical neoplasms, there was a significant association with the STI, marital status and smoking. Despite the integration of the detection of precancerous uterine cervical neoplasms lesions into health facilities in Gabon, uterine cervical neoplasms ranks second among women's cancers in terms of incidence and first in terms of mortality.

Dataset Information

In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions.

Publications

In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions.

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