AAVHSCs Showed Consistent Therapeutic Effect Across All Empty to Full Capsid Ratios, and Improved Benefit in the PKU Murine Model Compared to AAV5
BEDFORD, Mass., October 25, 2019 – Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the oral presentation of preclinical data related to its nuclease-free, homologous recombination-based, in vivo gene editing program for phenylketonuria (PKU) at the European Society of Gene & Cell Therapy (ESGCT) 27th Annual Congress. Homology also presented preclinical data that showed the effect of full and empty capsids on in vivo efficacy with Homology’s adeno-associated virus vectors derived from human hematopoietic stem cells (AAVHSCs), including its investigational phenylketonuria (PKU) gene therapy candidate HMI-102, and comparisons to an AAV5 PKU gene therapy vector.
“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 Albert Seymour, Ph.D., Chief Scientific Officer of Homology Medicines. “Importantly, the in vivo gene insertion was characterized and confirmed at the DNA level, demonstrating the efficiency and precision of editing supporting our PKU gene editing program.”
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.
Tim Kelly, Chief Technical Operations Officer of Homology Medicines, added, “In other studies presented here, we characterized the effect of full and empty capsids on in vivo efficacy with our proprietary AAVHSCs in a PKU disease model. We also reported that AAVHSCs reduced the levels of Phe to within the normal range regardless of full to empty ratios, and showed improved therapeutic activity in a PKU model compared to AAV5. These data suggest that AAVHSCs may be less sensitive to empty capsids, which is an important aspect for manufacturing.”
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.
About Homology Medicines, Inc.
Homology Medicines, Inc. is a genetic medicines company dedicated to transforming the lives of patients suffering from rare genetic diseases with significant unmet medical needs by curing the underlying cause of the disease. Homology’s proprietary platform is designed to utilize its human hematopoietic stem cell-derived adeno-associated virus vectors (AAVHSCs) to precisely and efficiently deliver genetic medicines in vivo either through a gene therapy or nuclease-free gene editing modality across a broad range of genetic disorders. Homology has a management team with a successful track record of discovering, developing and commercializing therapeutics with a particular focus on rare diseases, and intellectual property covering its suite of 15 AAVHSCs. Homology believes that its compelling preclinical data, scientific expertise, product development strategy, manufacturing capabilities and intellectual property position it as a leader in the development of genetic medicines. For more information, please visit www.homologymedicines.com.
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