Voyager Therapeutics Presents Advancements in Gene Therapy at ASGCT Annual Meeting

Voyager Therapeutics, Inc., a biotechnology firm focused on neurogenetic medicines, has unveiled new data from its TRACER™ capsid discovery platform and associated gene therapy programs. This information was presented at the American Society of Gene & Cell Therapy’s (ASGCT) 27th annual meeting.

The second-generation capsids developed through the TRACER platform, when delivered intravenously (IV), demonstrated improved blood-brain barrier (BBB) penetration, reduced liver targeting, and achieved transduction in 50-75% of cells in various brain regions, with up to 95% transduction in specific cell types such as Purkinje Neurons. Notably, a gene therapy in preclinical development for SOD1 amyotrophic lateral sclerosis (ALS) used a SOD1 RNAi transgene encapsulated in a second-generation capsid. This therapy reduced SOD1 messenger RNA (mRNA) expression by up to 80% in non-human primate (NHP) spinal cord motor neurons following a single IV dose of 3E13 vg/kg. These capsids' potential for translational use was supported by data across several species, including mice and multiple NHP species, and demonstrated binding to Alkaline Phosphatase (ALPL) in various species and human cells. These findings were emphasized in an oral presentation and several posters at the ASGCT meeting.

Dr. Todd Carter, Chief Scientific Officer of Voyager Therapeutics, highlighted the extensive validation of TRACER capsids for CNS gene therapy, based on results from species, capsid generations, and disease models. This success has enabled the selection of three development candidates in Voyager’s gene therapy programs targeting neurological diseases, with investigational new drug (IND) filings expected in 2025.

Voyager’s TRACER capsid discovery platform has led to the evolution of a second generation of capsids that offer enhanced CNS tropism and liver detargeting. In an NHP model, these capsids showed significant transgene expression in up to 65% of neurons and 97% of astrocytes across different brain regions. Additionally, a SOD1 RNAi transgene, when delivered via these second-generation capsids, effectively reduced SOD1 mRNA expression in NHP spinal cord motor neurons.

The potential of these capsids is supported by data from mice and various NHP models, as well as their binding to ALPL, a conserved receptor at the BBB that enhances brain tropism. Voyager’s advancements in wholly owned CNS gene therapy programs include an investigational tau silencing gene therapy for tauopathies and a gene therapy for SOD1-ALS, both demonstrating promising preclinical results and slated for IND filings in the coming years.

In terms of mechanism and cross-species translation, Voyager identified a highly conserved receptor utilized by engineered BBB-penetrant AAV capsids. This discovery marks a significant step forward in developing targeted CNS therapeutics. Additionally, Voyager developed a transcytosis model to better understand VCAP-102’s enhanced brain tropism, showcasing efficient transcytosis in cultured cells.

Voyager also evaluated VCAP-102 across various species, including mice, marmosets, African Green Monkeys, and Cynomolgus macaques, noting higher biodistribution and widespread transgene expression in the CNS compared to AAV9. This supports the capsid’s potential translatability to humans.

Voyager has addressed challenges in capsid variant characterization through a multiplexed reporter protein tagging platform, enabling simultaneous analysis of multiple capsid variants in a single animal model. Additionally, new TRACER-engineered AAV capsids have been developed to evade pre-existing neutralizing antibodies, potentially increasing patient eligibility for gene therapies.

Moreover, Voyager employs machine learning to predict capsid production fitness, aiding in the development of high-production-fit libraries. Comparisons of ultracentrifugation and chromatographic methods for enhancing AAV vector manufacturing were also conducted, and an internally developed HEK293 cell line was introduced to optimize the production of novel capsids with enhanced brain tropism.

The TRACER™ Capsid Discovery Platform is an RNA-based screening platform that enables rapid discovery of novel AAV capsids, facilitating gene therapy. This platform has yielded multiple capsid families with broad CNS region and cell type transduction following intravenous delivery in preclinical studies, leading to several development candidates in Voyager’s gene therapy programs.