Sustained Correction of a Murine Model of Phenylketonuria following a Single Intravenous Administration of AAVHSC15-PAH
| Autor: | Minglun Wang, Hillard Rubin, Jason Lotterhand, Omar L. Francone, Maria Lobikin, Seemin Seher Ahmed, Albert B. Seymour, Diana Lamppu, Laura Adamson-Small, Serena Nicole Dollive, Jeff L. Ellsworth, Teresa Leah Wright, Nancy Avila, Arnold Sengooba, Deiby Faulkner |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 Phenylalanine hydroxylase Genetic enhancement Metabolite Transgene Phenylalanine Pharmacology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics medicine lcsh:QH573-671 Tyrosine Molecular Biology chemistry.chemical_classification biology lcsh:Cytology business.industry medicine.disease lcsh:Genetics 030104 developmental biology Enzyme chemistry Inborn error of metabolism 030220 oncology & carcinogenesis biology.protein Molecular Medicine business |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 568-580 (2020) |
| ISSN: | 2329-0501 |
| Popis: | Phenylketonuria is an inborn error of metabolism caused by loss of function of the liver-expressed enzyme phenylalanine hydroxylase and is characterized by elevated systemic phenylalanine levels that are neurotoxic. Current therapies do not address the underlying genetic disease or restore the natural metabolic pathway resulting in the conversion of phenylalanine to tyrosine. A family of hepatotropic clade F adeno-associated viruses (AAVs) was isolated from human CD34+ hematopoietic stem cells (HSCs) and one (AAVHSC15) was utilized to deliver a vector to correct the phenylketonuria phenotype in Pahenu2 mice. The AAVHSC15 vector containing a codon-optimized form of the human phenylalanine hydroxylase cDNA was administered as a single intravenous dose to Pahenu2 mice maintained on a phenylalanine-containing normal chow diet. Optimization of the transgene resulted in a vector that produced a sustained reduction in serum phenylalanine and normalized tyrosine levels for the lifespan of Pahenu2 mice. Brain levels of phenylalanine and the downstream serotonin metabolite 5-hydroxyindoleacetic acid were restored. In addition, the coat color of treated mice darkened following treatment, indicating restoration of the phenylalanine metabolic pathway. Taken together, these data support the potential of an AAVHSC15-based gene therapy as an investigational therapeutic for phenylketonuria patients. Single administration of AAVHSC15-PAH (HMI-102) produced a sustained reduction in phenylalanine (Phe), the key biomarker in management of PKU, and an increase in tyrosine, a Phe metabolite and precursor to neurotransmitters, over the lifespan of the murine model. Brain Phe, 5-HIAA, and coat color normalized, further indicating metabolic pathway restoration. |
| Databáze: | OpenAIRE |
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