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      Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model

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          Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR). Like familial hypercholesterolaemia patients, our familial hypercholesterolaemia liver chimeric mice develop hypercholesterolaemia and a 'humanized‘ serum profile, including expression of the emerging drug targets cholesteryl ester transfer protein and apolipoprotein (a), for which no genes exist in mice. We go on to replace the missing LDLR in familial hypercholesterolaemia liver chimeric mice using an adeno-associated virus 9-based gene therapy and restore normal lipoprotein profiles after administration of a single dose. Our study marks the first time a human metabolic disease is induced in an experimental animal model by human hepatocyte transplantation and treated by gene therapy. Such xenograft platforms offer the ability to validate human experimental therapies and may foster their rapid translation into the clinic.


          Familial hypercholesterolemia (FH) is a congenital disease associated with high plasma cholesterol levels. Here, the authors recapitulate FH in chimeric mice, in which livers are repopulated with hepatocytes from an FH patient, and successfully correct the disease using adenovirus-mediated gene therapy.

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          Most cited references 39

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          Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy.

          Tissues from rhesus monkeys were screened by PCR for the presence of sequences homologous to known adeno-associated virus (AAV) serotypes 1-6. DNA spanning entire rep-cap ORFs from two novel AAVs, called AAV7 and AAV8, were isolated. Sequence comparisons among these and previously described AAVs revealed the greatest divergence in capsid proteins. AAV7 and AAV8 were not neutralized by heterologous antisera raised to the other serotypes. Neutralizing antibodies to AAV7 and AAV8 were rare in human serum and, when present, were low in activity. Vectors formed with capsids from AAV7 and AAV8 were generated by using rep and inverted terminal repeats (ITRs) from AAV2 and were compared with similarly constructed vectors made from capsids of AAV1, AAV2, and AAV5. Murine models of skeletal muscle and liver-directed gene transfer were used to evaluate relative vector performance. AAV7 vectors demonstrated efficiencies of transgene expression in skeletal muscle equivalent to that observed with AAV1, the most efficient known serotype for this application. In liver, transgene expression was 10- to 100-fold higher with AAV8 than observed with other serotypes. This improved efficiency correlated with increased persistence of vector DNA and higher number of transduced hepatocytes. The efficiency of AAV8 vector for liver-directed gene transfer of factor IX was not impacted by preimmunization with the other AAV serotypes. Vectors based on these novel, nonhuman primate AAVs should be considered for human gene therapy because of low reactivity to antibodies directed to human AAVs and because gene transfer efficiency in muscle was similar to that obtained with the best known serotype, whereas, in liver, gene transfer was substantially higher than previously described.
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            Clades of Adeno-associated viruses are widely disseminated in human tissues.

            The potential for using Adeno-associated virus (AAV) as a vector for human gene therapy has stimulated interest in the Dependovirus genus. Serologic data suggest that AAV infections are prevalent in humans, although analyses of viruses and viral sequences from clinical samples are extremely limited. Molecular techniques were used in this study to successfully detect endogenous AAV sequences in 18% of all human tissues screened, with the liver and bone marrow being the most predominant sites. Sequence characterization of rescued AAV DNAs indicated a diverse array of molecular forms which segregate into clades whose members share functional and serologic similarities. One of the most predominant human clades is a hybrid of two previously described AAV serotypes, while another clade was found in humans and several species of nonhuman primates, suggesting a cross-species transmission of this virus. These data provide important information regarding the biology of parvoviruses in humans and their use as gene therapy vectors.
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              Preparation of isolated rat liver cells.

               Per Seglen (1975)

                Author and article information

                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                17 June 2015
                : 6
                [1 ]Center for Cell and Gene Therapy, Department of Molecular and Cellular Biology, Baylor College of Medicine , Houston, Texas 77030, USA
                [2 ]Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, USA
                [3 ]Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Diabetes and Endocrinology Research Center, Baylor College of Medicine , Houston, Texas 77030, USA
                [4 ]Molecular and Cellular Biology Graduate Program, Baylor College of Medicine , Houston, Texas 77030, USA
                [5 ]Graduate Program in Developmental Biology, Baylor College of Medicine , Houston, Texas 77030, USA
                [6 ]Department of Pediatrics, Department of Molecular and Cellular Biology , Houston, Texas 77030, USA
                [7 ]Dan L. Duncan Cancer Center, and Alkek Center for Molecular Discovery, Baylor College of Medicine , Houston, Texas 77030, USA
                [8 ]Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine , Houston, Texas 77030, USA
                [9 ]Department of Pediatrics, Texas Children's Hospital , Houston, Texas 77030, USA
                [10 ]Department of Surgery, Texas Children's Hospital , Houston, Texas 77030, USA
                [11 ]Department of Molecular Physiology and Biophysics, Baylor College of Medicine , Houston, Texas 77030, USA
                Author notes

                These authors contributed equally to this work

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