AAVHSC16 Biodistribution Properties in Preclinical Models Demonstrated Potential for Systemic Delivery of Genetic Medicines to Brain, Heart and Muscle
BEDFORD, Mass., July 05, 2022 -- Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the peer-reviewed publication of data showing that AAVHSC16, one of the capsids in its family of 15 naturally occurring AAVHSCs, demonstrated low levels of tropism to the liver while maintaining robust distribution to the central nervous system (CNS) and peripheral organs following a single I.V. administration in preclinical models. The Company believes that its unique properties, with high levels of tropism to the brain, heart and muscle, and no elevations in liver enzymes, could make AAVHSC16 an attractive capsid for new disease indications with Homology’s genetic medicines platform.
“Our ongoing efforts to fully characterize our family of 15 naturally occurring AAVHSCs as it relates to biodistribution, tissue tropism and the role different features of the capsids play, continues to reveal their unique profiles that allow us to best select capsids for different diseases,” said Albert Seymour, Ph.D., President and Chief Scientific Officer of Homology Medicines. “In the case of AAVHSC16 with its ability to reach key tissues without targeting the liver in preclinical models, we can potentially expand into additional disease areas where we want to deliver to the CNS, cardiac tissue, or muscle while avoiding exposure in the liver. By continuing to publish our discoveries about the unique structure and function of our AAVHSCs, we believe we can contribute to the field’s greater understanding and development of AAV-based therapies that will ultimately benefit more patients.”
Homology’s AAVHSC capsids differ from each other by one to four amino acids, resulting in differences in biodistribution and transduction efficiencies. As described in the manuscript, AAVHSC16 has two unique amino acids, 501I and 706C, in addition to 505R that is shared across six AAVHSC serotypes. A series of experiments demonstrated that these amino acids contribute to AAVHSC16’s unique properties, which include significantly reduced liver tropism compared to other AAVs, no liver enzyme elevations, and high tissue tropism to the CNS and other peripheral organs. Specifically, these data demonstrated:
Naturally Occurring Variations in AAVHSC16 Alter Cellular Binding Affinity In Vitro
- AAVHSC16 does not share the galactose (a type of glycan) binding feature of other AAVHSCs and Clade F AAVs in vitro. AAVHSC16 did not show improved binding or a difference in number of vector genomes (vgs) or eGFP expression in cells with terminally exposed galactose, while other AAVHSCs tested did.
- The combination of the unique naturally occurring amino acids at positions 501I and 505R in AAVHSC16 were shown to contribute to reduced galactose-binding.
AAVHSC16 Has Significantly Reduced Liver Transduction in In Vivo and In Vitro Models, with High Tropism to other Tissues Following a Single I.V. Administration
- In murine models, a single I.V. administration of AAVHSC16 showed significantly lower levels of liver tropism compared to AAVHSC15 and AAV9. The liver was the only organ with significant differences as AAVHSC16 demonstrated high levels of tropism to all other organs evaluated, including the brain, heart and muscle; these levels were comparable to those observed with AAVHSC15 and AAV9.
- Further, in non-human primates (NHPs), a single I.V. administration of AAVHSC16 resulted in substantially lower liver expression than AAVHSC15, while maintaining high and equivalent levels of transduction in the brain, heart and muscle.
- In vitro data also showed that AAVHSC16 led to lower expression in primary human liver cells compared to other tested wild type AAVHSCs and AAV9, and it revealed that AAVHSC16’s 706 residue was the main contributor to this outcome.
AAVHSC16 Did Not Lead to Elevations in Liver Function Tests
- In NHPs, a single I.V. administration of AAVHSC16 at 7E+13 and 1E+14 vg/kg doses did not result in elevated ALT (alanine transaminase) or AST (aspartate transferase) levels at any timepoint post-dose compared to baseline levels or vehicle-treated controls.
- Comparing AAVHSC16 liver transduction and ALT and AST levels to AAV9 and other AAVHSCs further suggested that the lack of ALT and AST elevations with AAVHSC16 is associated with its lower liver tropism.
The publication, “Natural Variations in AAVHSC16 Significantly Reduce Liver Tropism and Maintain Broad Distribution to Periphery and CNS,” was peer-reviewed and published in the journal Molecular Therapy - Methods & Clinical Development. For more information, please click here or www.homologymedicines.com/publications.
About Homology Medicines, Inc.
Homology Medicines, Inc. is a clinical-stage genetic medicines company dedicated to transforming the lives of patients suffering from rare diseases by addressing the underlying cause of the disease. The Company’s clinical programs include HMI-102, an investigational gene therapy for adults with phenylketonuria (PKU); HMI-103, a gene editing candidate for PKU; and HMI-203, an investigational gene therapy for Hunter syndrome. Additional programs focus on metachromatic leukodystrophy (MLD), paroxysmal nocturnal hemoglobinuria (PNH) and other diseases. Homology’s proprietary platform is designed to utilize its family of 15 human hematopoietic stem cell-derived adeno-associated virus (AAVHSCs) vectors to precisely and efficiently deliver genetic medicines in vivo through a gene therapy or nuclease-free gene editing modality, as well as to deliver one-time gene therapy to produce antibodies throughout the body through the GTx-mAb platform. Homology has a management team with a successful track record of discovering, developing and commercializing therapeutics with a focus on rare diseases. Homology believes its initial clinical data and compelling preclinical data, scientific and product development expertise and broad intellectual property position the Company as a leader in genetic medicines. For more information, visit www.homologymedicines.com.
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding the potential to expand the application of AAVHSC16 to other disease areas; our expectations surrounding the potential, safety, and efficacy of our product candidates; the potential of our gene therapy and gene editing platforms; and our position as a leader in the development of genetic medicines. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies and clinical trials, and on general economic conditions; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; failure to identify additional product candidates and develop or commercialize marketable products; the early stage of our development efforts; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process; interim, topline and preliminary data may change as more patient data become available, and are subject to audit and verification procedures that could result in material changes in the final data; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties, including for the manufacture of materials for our research programs, preclinical and clinical studies; failure to obtain U.S. or international marketing approval; ongoing regulatory obligations; effects of significant competition; unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives; product liability lawsuits; securities class action litigation; failure to attract, retain and motivate qualified personnel; the possibility of system failures or security breaches; risks relating to intellectual property; risks associated with international operations, such as political and economic instability, including in light of the conflict between Russia and Ukraine; and significant costs incurred as a result of operating as a public company. These and other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, and our other filings with the Securities and Exchange Commission (SEC) could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change.