AAVHSC 17 / Homology Medicines - LARVOL DELTA

Targeted Approach to Immunosuppression with AAV Gene Therapy: Nonclinical Support of Clinical Approaches (ASGCT 2023) - P1 | "The calcineurin inhibitor, tacrolimus (Prograf®), and the corticosteroid, dexamethasone, were administered prophylactically for immunosuppression, followed by a single intravenous (I.V.) dose of rAAVHSC17 expressing human phenylalanine hydroxylase (rAAVHSC17-PAH). The introduction of a T-cell inhibitor tacrolimus allows for a potential shortening of the duration of exposure to high dose corticosteroids and a more rapid taper. This combination therapy is anticipated to decrease the development of nAb, optimize transgene expression and reduce the adverse events related to corticosteroid therapy."

Clinical • Gene therapy • Cardiovascular • CNS Disorders • Diabetes • Gene Therapies • Hunter Syndrome • Hypertension • Insomnia • Metabolic Disorders • Osteoporosis • Phenylketonuria • Psychiatry • Rare Diseases • Rheumatology • Sleep Disorder

Re-Dosing of Liver-Targeted AAV within and across Clades in Mice: Effects of Neutralizing Antibodies and Vector-Specific Factors (ASGCT 2023) - "In the first study, the first cohort of mice were dosed intravenously (I.V.) at 5E+12 vg/kg with an AAVHSC15 (Clade F) vector expressing phenylalanine hydroxylase (PAH) and then after 4 weeks, the mice were re-dosed I.V. at 5E+13 vg/kg with AAV5, AAV6 (Clade A), AAV8 (Clade E), AAV9 (Clade F), AAVHSC15 (Clade F), or AAVHSC17 (Clade F) vectors expressing Factor IX (FIX)...It is possible that re-dosing with certain clades is dependent not just upon nAb activity, but on the capacity of the liver to be transduced when high levels of AAV vgs are present. Further studies are warranted for translation into human patients."

Preclinical • Gene Therapies • Genetic Disorders • Inflammation • Metabolic Disorders • Pediatrics • Phenylketonuria • Rare Diseases

Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates. (PubMed, PLoS One) - "The biodistribution of AAVHSC7, AAVHSC15, and AAVHSC17 following systemic delivery was assessed in cynomolgus macaques (Macaca fascicularis)...Biodistribution of AAVHSC vector genomes in the central and peripheral organs generally correlated with eGFP staining and were highest in the liver for all AAVHSC vectors tested. These data demonstrate that AAVHSCs have broad tissue tropism and cross the blood-nerve and blood-brain-barriers following systemic delivery in nonhuman primates, making them suitable gene editing or gene transfer vectors for therapeutic application in human genetic diseases."

Journal

Genome Editing by Clade F AAV Homology Donors in the Presence and Absence of Site-Specific DNA Breaks (ASGCT 2019) - "...To further examine this property, we packaged donor genomes with homology for the human CCR5 or AAVS1 loci into AAV vectors using capsids from AAV6, AAV9 or AAV9-G505R, which contains the reported amino acid sequence of AAVHSC13 and AAVHSC17 (Smith et al...(2018), whose expression would require insertion downstream of a promoter and splice donor (AAVS1-SA-2A-GFP). In K562 cells transduced with the CCR5-PGK-GFP series of vectors, all populations initially contained GFP+ cells, but rapidly lost GFP expression to be"