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Voyager Therapeutics, Inc., a gene therapy company developing life-changing treatments and next-generation adeno-associated virus (AAV) capsids, presents new preclinical data on a family of AAV9-derived TRACER capsids demonstrating cross-species central nervous system (CNS) transduction. The company is also scheduled to report updated results from preclinical gene therapy programmes in GBA1, tauopathies, and SOD1 ALS. These results presented at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting in Washington, D.C.
Voyager’s TRACER capsid discovery platform has identified a novel AAV9-derived capsid, VCAP-102, which demonstrated 50-fold better transduction in mice and 60-fold better transduction in non-human primates (NHPs) versus conventional AAV9 capsids, following intravenous (IV) administration. While other TRACER capsids have shown strong neuronal delivery, preclinical data in this study also demonstrated that VCAP-102 and other TRACER capsids showed preferential tropism for glial cells in mice.
“These TRACER findings are important because demonstrating equivalent cross-species functionality is critical to increasing a capsid’s potential for translation into humans,” said Mathieu Nonnenmacher, Ph.D., vice president of capsid discovery at Voyager. “Furthermore, the glial tropism observed in this AAV9-derived capsid family may allow us to address CNS indications that would benefit from non-neuronal cell transduction.”
Key Results -- Top variants from the capsid family exhibited increased blood brain barrier (BBB)-penetrance across NHP species and mice; Top variants showed preferential transduction of glial cells in mice; Certain variants displayed significant detargeting from peripheral organs, including the dorsal root ganglia and liver.
Voyager presents preclinical data demonstrating improvements in physiologic parameters across pipeline programs involving CNS targets of interest: GBA1, tauopathies, and SOD1 ALS.
“The positive data scheduled to be reported at ASGCT support further development of Voyager’s CNS gene therapy programs that have significant opportunity to provide patient benefit,” said Todd Carter, Ph.D., senior vice president of Research at Voyager. “Voyager programs for GBA1, vectorized antibodies targeting tau, and SOD1 ALS leverage our expertise across payload modalities and differentiated delivery strategies to develop genetic medicines that safely achieve therapeutic benefit in preclinical models.”
GBA1 -- Key Results: Multiple transgenes for the optimal expression of glucocerebrosidase 1 (GBA1), the gene encoding the lysosomal enzyme glucoslyceramidase (GCase), were characterized in both in vitro and in vivo mouse models.
GBA1 transgenes using a BBB-penetrant AAV capsid delivered therapeutically-relevant levels of GCase to multiple brain regions in mouse models, following a single IV dose.
Tauopathies -- Key Results: Systemic dosing of a vectorized anti-tau antibody in mouse models resulted in reduced tau pathology and may represent a new single-dose IV therapeutic strategy for various tauopathies.
The antibody demonstrated robust efficacy in vectorized (vTau) and passive forms in a hippocampal seeding mouse model of Alzheimer’s disease.
Treatment with vTau resulted in significant reduction of tau pathology in CNS regions of a primary tauopathy mouse model.
When delivered passively, the antibody exhibited a trend of reduction in tau pathology in CNS regions of an intrinsic mouse model.
SOD1 ALS -- Key Results: IV delivery of a BBB-penetrant AAV9-derived capsid containing superoxide dismutase 1a (SOD1)-targeting RNAi gene therapy dramatically improved motor performance and survival in a SOD1- amyotrophic lateral sclerosis (ALS) mouse model.
Robust knockdown of SOD1 in all levels of the spinal cord was observed in a SOD1-ALS mouse model.
Data support preclinical development of an IV RNAi gene therapy using a novel BBB-penetrant capsid in primates.
Voyager’s TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) capsid discovery platform is a broadly applicable, RNA-based screening platform that enables rapid discovery of AAV capsids with robust penetration of the blood brain barrier and enhanced CNS tropism in multiple species, including non-human primates (NHPs). TRACER generated capsids have demonstrated superior and widespread gene expression in the CNS compared to conventional AAV capsids as well as cell- and tissue-specific transduction, including to areas of the brain that have been traditionally difficult to reach. Separate results have demonstrated the enhanced ability of certain capsids to target cardiac muscle and to de-target the dorsal root ganglia. Voyager is expanding its library of AAV capsids optimized to deliver diverse therapeutic payloads to address a broad range of CNS and other diseases.
Voyager Therapeutics is leading the next generation of AAV gene therapy to unlock the potential of the modality to treat devastating diseases.
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