RESUMO
Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. Loss of alanine glyoxylate aminotransferase (AGT) function to convert intermediate metabolite glyoxylate to glycine causes the accumulation and reduction of glyoxylate to glycolate, which eventually is oxidized to oxalate. Excess oxalate in PH1 patients leads to the formation and deposition of calcium oxalate crystals in the kidney and urinary tract. Oxalate crystal deposition causes a decline in renal function, systemic oxalosis, and eventually end-stage renal disease and premature death. mRNA-based therapies are a new class of drugs that work by replacing the missing enzyme. mRNA encoding AGT has the potential to restore normal glyoxylate to glycine metabolism, thus preventing the buildup of calcium oxalate in various organs. Panels of codon-optimized AGT mRNA constructs were screened in vitro and in wild-type mice for the production of a functional AGT enzyme. Two human constructs, wild-type and engineered AGT (RHEAM), were tested in Agxt-/- mice. Repeat dosing in Agxt-/- mice resulted in a 40% reduction in urinary oxalate, suggesting therapeutic benefit. These studies suggest that mRNA encoding AGT led to increased expression and activity of the AGT enzyme in liver that translated into decrease in urinary oxalate levels. Taken together, our data indicate that AGT mRNA may have the potential to be developed into a therapeutic for PH1.
Assuntos
Hiperoxalúria Primária/genética , Fígado/efeitos dos fármacos , RNA Mensageiro/farmacologia , Transaminases/farmacologia , Animais , Modelos Animais de Doenças , Vetores Genéticos/genética , Vetores Genéticos/farmacologia , Glioxilatos/metabolismo , Humanos , Hiperoxalúria Primária/terapia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , Oxalatos/metabolismo , RNA Mensageiro/genética , Transaminases/genéticaRESUMO
Crigler-Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine-diphosphate-glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1-modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first-in-human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First-in-human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.
Assuntos
Síndrome de Crigler-Najjar/terapia , Glucuronosiltransferase/genética , RNA/administração & dosagem , RNA/farmacocinética , Animais , Bilirrubina/sangue , Síndrome de Crigler-Najjar/genética , Síndrome de Crigler-Najjar/metabolismo , Modelos Animais de Doenças , Terapia Genética , Glucuronosiltransferase/metabolismo , Humanos , Fígado/química , Modelos Teóricos , Nanopartículas , RNA Mensageiro/sangue , RNA Mensageiro/metabolismo , Ratos , Ratos Gunn , Resultado do TratamentoRESUMO
Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.
