Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Amônia/sangue , Doença da Deficiência de Ornitina Carbomoiltransferase , Ureia/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Antimetabólitos/uso terapêutico , Pré-Escolar , Combinação de Medicamentos , Humanos , Lactente , Recém-Nascido , Fenilacetatos/uso terapêutico , Benzoato de Sódio/uso terapêuticoRESUMO
OBJECTIVE: The purpose of this report was to provide detailed information on the safety and feasibility of surgical procedures associated with the first ex vivo liver-directed gene therapy trial for the treatment of vivo gene therapy for homozygous familial hypercholesterolemia (FH). SUMMARY BACKGROUND DATA: Familial hypercholesterolemia is an autosomal dominant disease in which the gene encoding the low density lipoprotein receptor is defective. Patients homozygous for this mutation have extraordinarily high levels of cholesterol and accelerated atherosclerosis and die prematurely of myocardial infarction. The concept of liver-directed gene therapy was based on the report of normalization of cholesterol levels by orthotopic cardiac/liver transplant in a child with homozygous FH. METHODS: Five patients with homozygous FH were selected for inclusion in this trial. The patients underwent hepatic resection and placement of a portal venous catheter. Primary hepatocytes cultures were prepared from the resected liver and transduced with a recombinant retrovirus encoding the gene for the human low density lipoprotein receptor. The genetically modified cells were then transplanted into the liver through the portal venous catheter. RESULTS: Numerous clinical, laboratory, and radiologic parameters were analyzed. Elevations of the hepatic transaminases and leukocyte counts and a decline in hematocrit count were noted. Transient elevations of the portal pressure were observed during cell infusion. No major perioperative morbidity--specifically, myocardial infarct, perioperative hemorrhage, or portal vein thrombosis--or death occurred as a result of this protocol. CONCLUSION: Liver-directed ex vivo gene therapy can be accomplished safely in humans and is appropriate for selected patients.
Assuntos
Terapia Genética/métodos , Homozigoto , Hiperlipoproteinemia Tipo II/genética , Adulto , Canadá/etnologia , Criança , China/etnologia , Colômbia/etnologia , Terapia Combinada , Chipre/etnologia , Estudos de Viabilidade , Feminino , Hepatectomia , Humanos , Hiperlipoproteinemia Tipo II/etnologia , Hiperlipoproteinemia Tipo II/terapia , Fígado , MasculinoRESUMO
We identified 80 patients with nephropathic cystinosis older than age 10 years in the United States and Canada. The oldest reported individual was 26 years of age. Ninety percent of patients had received at least one renal allograft. Age at the time of first transplant varied between 7 and 17 years (mean 10.0 years). Almost three fourths of the patients required thyroid replacement, 27% had splenomegaly, and 42% had hepatomegaly. Photophobia was noted in 86% of patients, decreased visual acuity in 32%, and corneal ulcerations in 15%. Neurologic involvement, renal osteodystrophy, and diabetes mellitus were unusual. All these late complications of nephropathic cystinosis contribute to a description of the natural history of the disease and provide a rationale for the therapeutic use of cystine-depleting agents after renal transplantation.
Assuntos
Cistinose/complicações , Adolescente , Adulto , Criança , Cistina/metabolismo , Cistinose/metabolismo , Oftalmopatias/etiologia , Hepatomegalia/etiologia , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Esplenomegalia/etiologia , Transtornos da Visão/etiologiaAssuntos
Cistinose/genética , Falência Renal Crônica/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fatores de TempoRESUMO
The effects of branched-chain amino acid metabolites on granulocyte-macrophage progenitor cell proliferation in marrow culture are reported. Isovalerate and propionate profoundly suppress granulopoiesis at both 3.2 and 6.4 mM concentrations, whereas methylmalonate and other metabolites suppress to a lesser degree. The parent branched-chain amino acids leucine, isoleucine, and valine do not suppress in vitro granulopoiesis at similar concentrations. Because the concentrations of the organic acids tested fall within the pathophysiologic ranges observed in patients with isovaleric, propionic, and methylmalonic acidemias, we suggest that elevated in vivo levels of isovalerate, propionate, and to a lesser degree methylmalonate are responsible for the neutropenia observed in these disorders.