Tau-targeting therapies focus on ridding the brain of the toxic tau protein that wreaks havoc in neurodegenerative diseases like Alzheimer’s disease (AD). Drugs currently under investigation to target tau include immunotherapies, small molecule tau inhibitors, antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) and gene therapy. Gene therapy options, in particular, have the exciting potential to offer broad and durable reductions in tau in just one dose.
“A gene therapy approach turns the body into its own medicine-producing factory, enabling sustained production of genetic instructions that is designed to lower the production of tau,” Raj Rajagovindan, Vice President of Translational Medicine at Voyager Therapeutics, told DDN.
Voyager recently released results of their good laboratory practice (GLP) data in non-human primates for their tau-targeting gene therapy, VY1706. With just one dose, the therapy resulted in tau reductions of up to 75 percent in multiple brain areas.
If successful in human studies, Voyager’s gene therapy could offer several advantages over other tau-targeting therapies currently under investigation. Biogen’s tau-targeting antisense oligonucleotide (ASO) therapy for AD, which recently missed its Phase 2 primary endpoint but demonstrated initial proof of concept across secondary endpoints, is expected to advance into Phase 3 development. However, the treatment requires invasive injections into the fluid-filled space around the spinal cord given every three to six months for 18 months.In contrast, Voyager’s vectorized siRNA is delivered intravenously just once and successfully crosses the blood-brain barrier (BBB) in preclinical models.
“We have seen broad and efficient brain delivery in both rodents and non-human primates, which increases our confidence that the biology underlying this technology will translate well to humans,” said Rajagovindan.
Making it to the brain
“One of the biggest challenges in treating brain diseases is getting enough medicine into the brain,” said Rajagovindan.
We have seen broad and efficient brain delivery in both rodents and non-human primates, which increases our confidence that the biology underlying this technology will translate well to humans.
—Raj Rajagovindan, Voyager Therapeutics
VY1706 is so successful at crossing the BBB so far in preclinical models because it relies on a different method than typical gene therapies delivered via AAVs. Instead, Voyager uses its proprietary BBB-crossing TRACER capsids that are designed to bind to ALPL (alkaline phosphatase), a vascular receptor in the brain. “By engaging ALPL, the capsid can cross the blood-brain barrier after a simple intravenous infusion and deliver the therapy broadly throughout the central nervous system,” noted Rajagovindan.
The GLP toxicology study showed that the drug reduced mRNA of the MAPT (microtubule-associated protein tau) gene and tau protein by up to 75 percent, which lasted six months. The drug was also well tolerated in the non-human primates, with no concerning side effects found in the brain, dorsal root ganglia, liver, or other major organs even at the highest doses. “We were also encouraged by the relatively lower liver exposure and lack of liver enzyme elevations often associated with systemic AAV therapies,” Rajagovindan said.
One and done
“For me, the most exciting aspect was seeing that a one-time intravenous treatment with VY1706 achieved broad delivery across the brain, produced robust tau lowering, and resulted in a favorable safety profile in non-human primates,” Rajagovindan told DDN.
With an Investigational New Drug (IND) application granted this past June, the company plans to advance VY1706 into a first-in-human study in the second half of 2026. The study will focus on investigating the safety, target engagement, and the possible effects of reducing tau on disease progression in AD.
“Success in the clinic with this approach, which combines a novel BBB-crossing capsid with a therapeutic genetic payload could help pave the way not only for Alzheimer's disease, but also open the door to a new generation of genetic medicines for neurological disorders that have historically been difficult to treat,” said Rajagovindan.
