Homology Medicines Presents Preclinical Data From Its Investigational PKU Gene Editing Program, Demonstrating Phenotypic Correction and Molecular Confirmation of Editing Precision
“The ability of AAVs to induce nuclease-free gene editing through homologous recombination has been established for decades, and here we presented data showing that our AAVHSCs induced in vivo targeted gene insertion into genomes using this natural DNA repair pathway in humanized and PKU murine models,” stated
Highlights from the oral presentation included:
Nuclease-Free In Vivo Gene Insertion in Murine Models
- A single administration of an AAHVSC gene editing vector demonstrated sustained reduction of Phe levels in a PKU murine model.
- In a humanized liver murine model, quantitative DNA measurements confirmed human hepatocyte-specific editing with HMI-103, Homology’s investigational human gene editing candidate, with no editing observed in murine hepatocytes, demonstrating species specificity of gene insertion.
- Next-generation sequencing demonstrated efficiency and fidelity of PAH gene integration, with no detection of insertions or deletions at the edited site.
- Long-read sequencing confirmed no inverted terminal repeat integration at edited alleles.
Highlights from the manufacturing poster included:
Impact of Full and Empty Particle Concentration on Product Quality and In Vivo Efficacy of HMI-102 in a Murine Model of PKU
- There were no significant differences in infectivity of investigational HMI-102 gene therapy candidate (packaged in AAVHSC15) across 10%, 20% and 40% DNA-containing preparations, with all preparations resulting in a therapeutic correction in a PKU murine model.
- AAVHSC15 packaged with the PAH gene, manufactured and purified to contain >95% DNA-containing particles, improved disease correction in a PKU murine model compared to AAV5 identically packaged, manufactured and dosed; the AAV5 vector was comparable to formulation buffer.
- AAVHSC15 corrected the PKU phenotype in the murine model with all vector preparations composed of 20% to 100% DNA-containing particles, while AAV5 only reduced serum Phe by 25% at the same vector preparations and dose.
- AAVHSC15 demonstrated increased mRNA and DNA in livers in a PKU murine model compared to AAV5 at 40% and 100% DNA-containing particles, as measured by in situ hybridization (ISH). ISH measurements and nucleic acid signal were comparable at the 40% and 100% ratios across each vector.
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About Phenylketonuria (PKU)
PKU is a rare, inherited inborn error of metabolism caused by mutations in the PAH gene. The current standard of care is a highly restrictive diet, but it is not always effective, and there are currently no treatments available that address the genetic defect in PKU. If left untreated, PKU can result in progressive and severe neurological impairment. PKU affects approximately 16,500 people in the U.S., and an estimated 350 newborns are diagnosed each year.
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|SVP, Corporate Communications
and Patient Advocacy
|Senior Director, Patient Advocacy
and Corporate Communications
Source: Homology Medicines, Inc.