In utero CRISPR-mediated therapeutic editing of genes
AssigneesThe Trustees of the University of Pennsylvania, The Children's Hospital of Philadelphia
InventorsKiran Musunuru, William H. Peranteau, Edward Morrisey
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Abstract
A method for in utero genome editing, the method comprising administering to a subject an adenoviral vector, wherein the subject is a fetus, the adenoviral vector comprising CRISPR-mediated base editor and a guide RNA (gRNA), the gRNA targeting a mutation in a therapeutic gene; and introducing a modified codon in the therapeutic gene by base editing the therapeutic gene, wherein the base editing is performed by the adenoviral vector, an adeno-associated viral vector or lipid based nanoparticle.
Claims16
A method for in utero genome editing in a fetal subject in need thereof, the method comprising:
- (a) administering to the fetal subject, a pharmaceutical composition comprising at least one of
- i) a lipid nanoparticle delivery vehicle;
- ii) an adenovirus (AV) vector;
- or
- iii) an adeno-associated virus (AAV) vector,
- wherein at least one of i), ii) or iii) comprise nucleic acids encoding a CRISPR-mediated base editor 3 (BE3) or base editor 4 (BE4) and a guide RNA (gRNA) comprising a protospacer adjacent motif (PAM), which upon expression in said subject, form a CRISPR complex at a target site present in a 4-hydroxyphenylpyruvate dioxygenase (Hpd) gene;
- and
- (b) introducing a modified codon at said target site in the Hpd gene by CRISPR complex mediated base editing for reducing Hpd expression, thereby treating, or reducing the risk of, hereditary tyrosinemia type I (HT1) disorder in said fetal subject, wherein said gRNA includes the nucleotide sequence of SEQ ID NO:
- 36, 5′-CATTCAACGTCACAACCACC-3′, an AGG PAM sequence and the editing is a C to T change on a sense strand encoding the Hpd gene at a mean editing rate of ˜15%.
Dependencies are inferred from the claim text.