Voyager Therapeutics, Inc. announced the presentation of data related to its TRACER?? capsid discovery platform and TRACER-driven gene therapy programs at the American Society of Gene & Cell Therapy's (ASGCT) 27th annual meeting. Second-generation, intravenously (IV)-delivered capsids, evolved through the TRACER platform, showed further enhanced blood-brain barrier (BBB) penetrance, greater liver detargeting, and transduction of 50-75% of cells across diverse brain regions, with upwards of 95% transduction in certain key cell types such as Purkinje Neurons.

Further, a gene therapy in preclinical development for SOD1 amyotrophic lateral sclerosis (ALS), which combines a SOD1 RNAi transgene packaged in a second-generation capsid, reduced SOD1 messenger RNA (mRNA) expression by up to 80% in non-human primate (NHP) spinal cord motor neurons following a single IV delivery at a clinically relevant dose of 3E13 vg/kg. The potential translatability of these capsids is supported by data across multiple species, including mice and multiple species of NHP, as well as binding to Alkaline Phosphatase (ALPL, formerly called Receptor X) in multiple species and in human cells. These data are highlighted in the oral presentation, ?Continued directed evolution of VCAP-101 and VCAP-102 identifies second generation capsids with increased brain tropism in non-human primates and mice (#119)?

on May 8, 2024, 4:30 p.m. ? 4:45 p.m. ET. Additional data demonstrating the potential translatability, activity against therapeutic targets, manufacturability and performance of Voyager?s TRACER capsids are being presented across 12 oral and poster presentations throughout the ASGCT meeting as follows: Second-Generation Capsids: Oral Presentation: Continued directed evolution of VCAP-101 and VCAP-102 identifies second generation capsids with increased brain tropism in non-human primates and mice (#119).

Applying its TRACER capsid discovery platform, Voyager has evolved a second generation of capsids with further optimized features, including central nervous system (CNS) tropism and liver detargeting, compared to VCAP-101 or VCAP-102 capsids. With low doses (3E13 vg/kg) delivered IV in an NHP model, Voyager?s second-generation capsids achieved transgene expression in up to 65% of neurons and up to 97% of astrocytes across diverse brain regions, including cortical and subcortical areas. A SOD1 RNAi transgene packaged in a second-generation capsid and delivered IV reduced SOD1 mRNA expression by up to 80% in NHP spinal cord motor neurons.

The potential translatability of Voyager?s capsids is supported by data across mice and multiple NHP models, as well as binding to ALPL, a highly conserved cell surface receptor expressed at the BBB that mediates enhanced brain tropism of Voyager?s capsids in multiple species and in human cells. Advancements in Wholly-Owned CNS Gene Therapy Programs: Intravenous administration of BBB-penetrant, MAPT-Silencing, AAV gene therapy provides broad and robust CNS Tau lowering in tauopathy mouse models (#1602). A single IV administration of a tau silencing gene therapy candidate in a mouse model expressing human tau resulted in dose-dependent increases in vector genomes and concomitant reductions in tau mRNA levels of up to 90%, which were associated with significant reductions (50-70%) in human tau protein levels across the brain.

Voyager anticipates filing an investigational new drug (IND) application in this program in 2026. Intravenous delivery of AAV gene therapy for the treatment of SOD1-ALS provides broad SOD1 lowering in NHP (#1647). A potent SOD1 RNAi transgene packaged in a novel TRACER?-evolved capsid and administered IV in NHPs led to a favorable safety profile and significant reductions of SOD1 mRNA in critical spinal cord and brain regions impacted in ALS, supporting continued development and advancement into clinical testing.

Voyager anticipates filing an IND application in this program in mid-2025. Mechanism of Action and Cross-Species Translation: Identification and characterization of a highly conserved cell surface receptor utilized by engineered BBB-penetrant AAV capsids with enhanced brain tropism in non-human primates and mice (#975). Voyager identified a highly conserved cell surface receptor that mediates enhanced brain tropism of the VCAP-101/102 engineered capsid class.

The discovery of a conserved cross-species receptor facilitating BBB passage by a novel engineered AAV capsid class represents a significant step forward in the development of targeted CNS therapeutics and provides a foundation for the rational design of next-generation AAV vectors. Establishment of a predictive transcytosis model to recapitulate capsid-receptor interaction and phenotype of BBB-penetrant AAV variants (#976). To further characterize the mechanism underlying VCAP-102?s enhanced brain tropism, Voyager developed a transcytosis model expressing the VCAP-102 receptor in cultured cells and demonstrated that VCAP-102 and second-generation capsids, but not the AAV9 capsid, exhibited efficient transcytosis.