| liver-tropic rAAV2/8 vectors |
A liver-tropic rAAV2/8 vectors + Vanillin Treatment |
Systemic delivery |
• Lifelong and permanent correction of the Pahenu2 allele in a portion of treated hepatocytes |
Department of Molecular and Medical Genetics, Oregon Health & Science |
Mol Ther Methods Clin Dev. 2019 December 24; 17:234–245 |
| • Partial restoration of liver PAH activity |
| • Substantial reduction of blood Phe |
| • Prevention of maternal PKU effects during breeding |
| AAV-base editor systems (CRISPR-Cas-associated base editors) |
An rAAV vectors CRISPR-Cas-associated base editors |
Systemic delivery |
• Restored physiological Phe blood levels |
Department Biology, Institute for Molecular Health Sciences, ETH Zürich |
Nat Med. 2018 October; 24 (10):1519–1525 |
| • Up to 63% mRNA correction rates |
| • Restoration of 65% PAH enzyme activity |
| • Reversion of hypopigmented phenotype |
| AAV-Anc80 |
The synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH |
Systemic delivery |
• A safely and durably PKU curation |
Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, United States. |
J Inherit Metab Dis. 2021 November; 44 (6):1369–1381 |
| • The significant and durable reduction of circulating Phe (nearly decreased to control levels in males) |
| • Reversion of hypopigmented phenotype |
| AAV8-PAL |
An rAAV8 viral vector expressing the humanized PAL under the control of human antitrypsin (hAAT) promoter |
Systemic delivery |
• Long-term HPA correction in both genders |
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China |
Mol Ther Methods Clin Dev. 2020 January 13; 19:507–517 |
| AAV2-PKU-5 and rAAV2-PKU-5/8 |
An rAAV vector containing the murine PAH cDNA |
Systemic delivery |
• Complete correction of HPA in both males and females with a rAAV8 vector |
Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zürich |
Gene Ther. 2006 April; 13 (7):587–93 |
| • Reversion of hypopigmented phenotype |
| ssAAV8/CAG-mPAH and scAAV/LP1-mPAH |
An AAV8-pseudotyped vector constructed with a self-complementary AAV (scAAV) genome |
Systemic delivery |
• Long duration of the treatment |
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan |
J Gene Med. 2011 February; 13 (2):114–22 |
| • Reduction of blood Phe to normal or near-normal levels for more than 1 year in both genders |
| AAV8-AAVR and the SaCas9 system |
Co-delivery of SaCas9/sgRNA/donor templates with AAVR via AAV8 vectors |
Systemic delivery |
• Dramatically increased AAV transduction efficiency in vitro and in vivo
|
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China |
Sci China Life Sci. 2022 April; 65 (4):718–730 |
| • Increased indel rate over 2-fold and homologous recombination rate over 15-fold for the correction of the single mutation in PahR408W mice |
| • Significantly decreased Phe level and ameliorated PKU symptom |
| rAAV2/8-hPAH |
A pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein |
Systemic delivery |
• Increased PAH activity (female: 65–70%; male: 90%) |
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea |
J Korean Med Sci. 2008 October; 23 (5):877–83 |
| • Plasma Phe concentration in female decreased to the normal value |
| • The offspring of the treated female PKU mice can rescue from the harmful effect of maternal HPA |
| • Reversion of hypopigmented phenotype |
| rAAV2/1-PAH-GTPCH-PTPS |
A rAAV2 pseudotype 1 vector expressing PAH along with GTPCH and 6-pyruvoyltetrahydrobiopterin synthase (PTPS) |
Gastrocnemius muscles injection |
• The stable and long-term reduction of blood Phe |
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich |
Mol Ther. 2008 April; 16 (4):673–81 |
| • Reversal of PKU-associated coat hypopigmentation |
| AAV2/1-PKU5, AAV2/2-PKU5, and AAV2/8-PKU5 |
Three different recombinant AAV2 genomes packaged with either serotype 1, 2, or 8 capsid were generated to express the PAH gene |
Gastrocnemius muscles injection |
• Restored liver PAH activity and Phe clearance (long-term clearance: AAV2/1-PKU5 and AAV2/8-PKU5 only) |
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zürich, CH-8032 Zürich, Switzerland |
Hum Gene Ther. 2010 April; 21 (4):463–77 |
| • Therapeutic correction in both genders (more effectively in males) |
| • Subsequent supplementation with synthetic tetrahydrobiopterin resulted in a transient decrease in blood phenylalanine in female after rAAV2/8 injection |
| AAV5/CAG-mPAH. |
A recombinant adeno-associated virus (AAV) vector carrying the murine PAH cDNA |
Systemic delivery |
• Completely normalized pf PHA phenotype |
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan |
Gene Ther. 2004 July; 11 (13):1081–6 |
| • Substantial blood Phe reduction in male |
| • Long-term correction of HPA |
| • Transduction ameliorated the PKU phenotype (reversed central nervous system dysfunctions and correction of hypopigmentation) |
| rAAV-mPAH-WPRE |
A rAAV-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector |
Systemic delivery |
• Rapid reduction of serum Phe levels |
Department of Biochemistry and Molecular Biology, PO Box 100245, College of Medicine, University of Florida, Gainesville, FL 32610, United States. |
Brain Res. 2007 January 5; 1127 (1):136–50 |
| • Reversed neuropathologic phenotypes |
| AAV8-miniSaCBE-PLUS-PKU |
A dual AAV strategy for in vivo delivery of base editors, in which deaminases were linked to Cas9 through the interaction of GCN4 peptide and its single chain variable fragment (scFv) antibody |
Systemic delivery |
• Up to 27.7% correction in vitro
|
Laboratory of Biotherapy, National Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Renmin Nanlu 17, Chengdu 610041, Sichuan, China |
Mol Ther Methods Clin Dev. 2022 Jan 7; 24: 230–240 |
| • Significantly rescued Phe metabolism and reduced urine phenyl ketone |
| • Rescue of hyperphenylalaninemia-associated syndromes in vivo (e.g. growth retardation, hypopigmentation, and behaviors) |
| AAVHSC15-PAH |
AAVHSC15: a clade F AAV isolated from human CD34+ hematopoietic stem cells (HSCs) AAVHSC15-PAH: The AAVHSC15 vector containing a codon-optimized form of the human phenylalanine hydroxylase cDNA |
Systemic delivery |
• Sustained reduction of serum Phe |
Research and Development, Homology Medicines, Patriots Park, Bedford, MA 01730, United States. |
Mol Ther Methods Clin Dev. 2020 March 13; 17:568–580 |
| • Sustained reduction in serum Phe and normalized tyrosine levels for the lifespan of Pahenu2 mice |
| • Restored brain levels of Phe and the downstream serotonin metabolite 5-hydroxyindoleacetic acid |
| • Reversal of PKU-associated coat hypopigmentation |
