Single AAV intravenous dose achieved widespread CNS distribution and sustained correction of GCase activity in multiple brain regions
CAMBRIDGE, MA, USA I October 20, 2021 I Voyager Therapeutics, Inc. (Nasdaq: VYGR), a gene therapy company developing life-changing treatments and next-generation adeno-associated virus (AAV) platform technologies, today announced the presentation of preclinical data demonstrating a single intravenous (IV) dose of its novel GBA1 gene replacement therapy achieved widespread distribution in the central nervous system (CNS) and peripheral tissues of mice, and substantially raised levels of the GCase enzyme in both in vivo and in vitro models. The results are available in an on-demand poster session throughout the virtual Congress of the European Society of Gene and Cell Therapy (ESGCT) Oct. 19-22.
“These encouraging preclinical results demonstrate that a single IV dose of GBA1 transgenes transported by a blood-brain barrier penetrant AAV capsid can effectively deliver therapeutically relevant levels of GBA1 protein to multiple brain regions of mice. Notably, the increase over endogenous GCase levels in the range of 300% – 660% is promising given increased GCase levels of 30-50 percent is anticipated to be clinically impactful,” said Glenn Pierce, M.D., Ph.D., interim chief scientific officer of Voyager. “These data show the potential that blood-brain barrier penetrant capsids may have to address severe neurological diseases as compared to loco-regional injection of AAV into the CNS and offer a solid foundation for continued investigation of this novel approach.”
Data presented at ESGCT demonstrates that AAV gene transfer of GBA1 transgenes in the cells of mouse models significantly reduced GCase enzyme activity and the accumulation of glycosphingolipids compared to non-AAV delivery. The treatment was well tolerated at all doses and resulted in the safe delivery of therapeutically relevant levels of GBA1 protein to multiple brain regions in mice. Key findings included:
- AAV vector optimized GBA1 achieved widespread distribution and sustained correction of GCase activity after IV administration in WT mice.
- Consistent voltage gated (VG) distribution and GCase activity was observed across the CNS following IV delivery.
- IV administration of BBB-penetrant capsid optimized GBA1 transgenes at a high dose resulted in approximately a 300% – 660% increase over endogenous GCase levels, suggesting the potential for dose reductions given that increased GCase activity of 30% – 50% is anticipated to be clinically impactful.
- Results validate GBA1 transgene-level DRG tissue-detargeting approach in vitro.
About GBA1 Mutations
The GBA1 gene encodes the lysosomal enzyme β-glucocerebrosidase (GCase) and GBA1 loss of function results in GCase deficit and cellular build-up of glycosphingolipid-substrate. In patients with GBA1 mutations, decreased levels of GCase can result in accumulations of lipids in the body, driving a number of diseases include Gaucher disease, Parkinson’s disease, and Lewy body dementia. While enzyme replacement therapies can have clinical impact, they fail to adequately cross the blood-brain barrier to address disease in the CNS.
About Voyager Therapeutics
Voyager Therapeutics (Nasdaq: VYGR) is leading the next generation of AAV gene therapy to unlock the potential of the technology to treat devastating diseases. Proprietary capsids born from the Company’s TRACER screening platform are powering a rich early-stage pipeline of new and second-generation programs and may elevate the field to overcome the limitations of conventional gene therapy vectors across neurologic disorders and other therapeutic areas.
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SOURCE: Voyager Therapeutics
