Voyager Therapeutics has achieved a significant milestone in gene therapy development with the publication of groundbreaking research demonstrating how alkaline phosphatase (ALPL) enables novel AAV capsids to cross the blood-brain barrier. The peer-reviewed study, titled "Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier," was published in Molecular Therapy and represents the first published evidence of ALPL's role in this critical transport mechanism.
Novel Capsid Shows Dramatic Improvement Over Standard AAV
The research centers on VCAP-102, a novel cross-species AAV capsid that demonstrates remarkable efficiency in gene delivery to the brain. In preclinical studies conducted in both rodents and non-human primates, VCAP-102 achieved 20- to 400-fold increased gene transfer across multiple brain regions compared to AAV9, the current standard for CNS gene therapy applications.
"Understanding ALPL and its ability to mediate transport across the blood-brain barrier has been foundational to the evolution of our gene therapy programs, two of which are advancing towards IND filings this year with a partner," said Mathieu Nonnenmacher, Ph.D., Vice President of Gene Therapy at Voyager.
The study identified ALPL as the primary receptor used by VCAP-102 to cross the blood-brain barrier, providing crucial mechanistic insights that could inform future therapeutic development. Additionally, the research confirmed that the ALPL capsid family binds and demonstrates transcytosis with human ALPL in a cell barrier in vitro model, suggesting strong potential for clinical translatability.
Second-Generation Capsids Achieve Unprecedented Transduction Rates
Building on the success of VCAP-102, Voyager has developed even more advanced capsid technologies. In multiple non-human primate studies utilizing various payloads, a single intravenous dose of 3e13 vg/kg of the company's second-generation CNS capsids achieved remarkable transduction rates across different brain regions and cell types:
- Up to 98% of dopaminergic neurons in substantia nigra
- Up to 94% of motor neurons in the spinal cord
- Up to 66% of neurons in the thalamus
- Up to 43% of neurons in the motor cortex
- 87-99% of astrocytes broadly across brain regions
These results represent a substantial advancement in the field of CNS gene therapy, where achieving efficient and widespread brain transduction has historically been a major challenge.
TRACER Platform Enables Rapid Capsid Discovery
The breakthrough capsids emerge from Voyager's proprietary TRACER™ (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) capsid discovery platform. This RNA-based screening platform enables rapid discovery of novel AAV capsids specifically designed for gene therapy applications targeting the central nervous system.
The TRACER platform has enabled Voyager to create multiple families of novel capsids that, following intravenous delivery in preclinical studies, harness the extensive vasculature of the CNS to cross the blood-brain barrier and transduce a broad range of CNS regions and cell types. In cross-species preclinical studies spanning rodents and multiple non-human primate species, intravenous delivery of TRACER-generated capsids resulted in widespread payload expression across the CNS at relatively low doses.
Multi-Modal Approach to Neurological Disease Treatment
Beyond viral gene therapy, Voyager is expanding its approach to include non-viral delivery methods. "In addition to speeding the evolution of novel capsid families, we are leveraging our work with ALPL and other receptors to deliver diverse classes of non-viral candidates into the CNS," said Todd Carter, Ph.D., Chief Scientific Officer of Voyager Therapeutics. "We believe this multi-modality approach, encompassing both viral and non-viral CNS delivery, is critical to addressing unmet needs in neurological disease."
Advancing Toward Clinical Applications
The company has evolved beyond first-generation capsids like VCAP-102 to develop next-generation capsids with enhanced brain transduction and liver de-targeting capabilities, as well as stealth capsids designed with immune-evading properties. This technological progression supports Voyager's pipeline of programs targeting major neurological diseases including Alzheimer's disease, Friedreich's ataxia, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).
Voyager is advancing these programs through both wholly-owned initiatives and partnerships with major pharmaceutical companies including Alexion, AstraZeneca Rare Disease, Novartis Pharma AG, and Neurocrine Biosciences. The company's research was previously presented at the American Society of Gene & Cell Therapy's 28th annual meeting, demonstrating the scientific community's recognition of these advances.
The publication in Molecular Therapy provides crucial validation of Voyager's approach and establishes ALPL as a key target for future CNS gene therapy development, potentially opening new avenues for treating previously intractable neurological diseases.
