Homology Medicines Announces Peer-Reviewed Publication on Novel Discovery of AAVHSC with Robust Distribution to the Central Nervous System and Peripheral Organs with Low Affinity for the Liver
July 05 2022 - 8:30AM
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.
Forward-Looking Statements 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.Company Contacts:Theresa McNeelyChief
Communications Officer and Patient
Advocatetmcneely@homologymedicines.com781-301-7277Media
Contact:Cara Mayfield Vice President, Patient Advocacy and
Corporate Communications cmayfield@homologymedicines.com
781-691-3510
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