Advances in AAV technology create new way forward for gene therapy in CNS diseases

While gene therapy has the potential to deliver life-changing treatment, it has had its share of setbacks and challenges. Because current gene therapies require high doses of delivery vector, dose-limiting toxicity has routinely been seen in most clinical trials involving systemic delivery. Even local delivery has had limited success due to inherent inefficiencies in viral delivery, particularly for diseases of the central nervous system (CNS). Encouragingly, advances in the field to improve viral tropism efficiency are yielding new technologies that present a promising way to deliver therapeutics safely and effectively across key regions of the brain.

Adeno-associated viruses (AAVs), harmless naturally occurring viruses, have been the delivery vehicle of choice for gene therapy for decades. Empty AAV protein shells (or capsids) can serve as molecular transporters of therapeutic genes or cargo to specific cells to treat disease. Clear progress has been made, but technical challenges around toxicity and reaching the CNS create continued bottlenecks to successful clinical translation – leading to more questions than answers, including how to target the right tissues at the right doses while detargeting undesired tissues (such as the dorsal root ganglia), how to achieve widespread distribution of AAVs at lower doses to broaden the therapeutic window, and how to ensure efficacy and safety.

Looking back, a key turning point for the gene therapy field came in 2016 when research out of Caltech showed that engineered capsids successfully penetrated the blood brain barrier (BBB) in specific strains of mice after intravenous (IV) delivery. However, this was not seen in other strains of mice or non-human primates (NHPs), raising concerns about translatability to humans.

It was then that Voyager Therapeutics began work on a new type of AAV capsid screening platform, dubbed TRACER™ (Tropism Redirection of AAV by Cell-type-specific Expression of RNA). To move beyond species-specific capsids, the platform was developed to start with cynomolgus monkeys to evaluate activity in primates, and includes screening in multiple NHP species and rodents to identify novel capsids with the greatest likelihood of successful translation into humans.

“The company completely revamped the way we screen AAV libraries by engineering a function-driven capsid evolution platform able to discover capsids that penetrate, and transduce multiple cell types in the CNS in non-human primates.”

- Mathieu Nonnenmacher

Ph.D., VP of Capsid Discovery at Voyager.

“The company completely revamped the way we screen AAV libraries by engineering a function-driven capsid evolution platform able to discover capsids that penetrate, and transduce multiple cell types in the CNS in non-human primates.” said Mathieu Nonnenmacher, Ph.D., VP of Capsid Discovery at Voyager. “We looked to cell-specific RNA expression to recover our capsid libraries, as we believe it offers a more realistic and accurate measure of functional transduction compared to existing DNA-based screening technologies.” 

In 2021, the company shared preliminary proof-of-concept for its initial TRACER AAV capsids at the American Society of Cell and Gene Therapy (ASGCT) Annual Meeting. Among the results from this first screening library was an AAV9-derived capsid that demonstrated widespread gene expression in the CNS of NHPs following a single IV dose, achieving 1,000 - 10,000-fold increased expression across multiple neuronal populations in several brain regions compared to a conventional AAV9 capsid.

 Dr. Garrett Heffner, Voyager’s VP of Gene Therapy, notes that the TRACER data presented at this year’s ASGCT meeting takes the company’s approach one step further. “We have validated the functional characteristics of our capsids across several species, which is critical to increasing the potential for clinical translation. And this is just a small portion of the potential for our platform that continues to add to a growing library of novel capsids,” said Dr. Heffner.

Other Voyager data shared at the meeting included a family of AAV9-derived capsids with unique tropism for glial cells in the brain, which demonstrated up to a 60-fold better transduction in NHPs, and up to a 50-fold better transduction in mice compared to conventional AAV9. The results suggest these next-generation capsids can enable better targeting of different cell types than previous TRACER capsids, and they may allow for the treatment of disorders that would benefit from glial cell specific transduction, in addition to disorders benefiting from the neuronal cell targeting observed with other TRACER capsid families. This unique targeting was successfully leveraged in a Voyager neuro-oncology study where these novel glial cell-trophic capsids were engineered to contain a vectorized anti-HER2 antibody. When administered as a single IV dose, the vector reduced HER2+ metastatic brain tumors, and extended survival in three independent animal models.

While AAV vectors derived from the AAV9 serotype have most commonly been evaluated for use as CNS gene therapies, capsids based on AAV serotype 5 present an attractive alternative because of a lower prevalence of preexisting neutralizing antibodies that disqualify patients from clinical trials. One TRACER AAV5-derived capsid demonstrated a 20-fold higher neuronal transduction in the brain and five-fold higher neuronal transduction in the spinal cord compared to a conventional AAV9 capsid in NHPs, together with partial detargeting of neurons in the dorsal root ganglia. This exciting finding could provide a path forward to treat a greater number of patients by allowing treatment of individuals that would otherwise have pre-existing immunity to other capsids.  

While continuing to iterate and improve the TRACER platform, the next step for Voyager and other companies exploring capsid technologies is advancing next generation AAV gene therapies to the clinic and demonstrating proof-of-concept in humans. Voyager says it plans to focus on monogenic diseases, well-validated targets, and established and proven modalities as payloads, seeking to follow an efficient and de-risked path for conducting clinical trials in patients with a range of neurodegenerative diseases.

To follow Voyager's journey towards unlocking the full potential of AAV gene therapy, visit voyagertherapeutics.com. 

This article was originally published as sponsored content for STATNews.