Fighting buildup of tau protein in Alzheimer’s by targeting RNA

Efforts to treat Alzheimer’s disease by targeting the peptide amyloid-β have largely failed so far, but researchers are also pursuing another target: tau protein. Like amyloid-β, tau aggregates in the brains of Alzheimer’s patients.

Until now, strategies against tau have mainly involved the use of antibodies and small-molecule drugs. But Timothy M. Miller and colleagues at Washington University in St. Louis are taking a different approach. “We are turning down the production of the tau gene,” Miller says.

As Alzheimer’s progresses, tau forms fibrous tangles inside neurons, beginning in brain regions important for navigation and memory and eventually spreading. To decrease tau levels in mice, Miller’s group uses antisense oligonucleotides, which are synthetic, chemically modified, single-stranded DNA molecules that bind complementarily to messenger RNA that codes for tau, shutting down tau protein production.

The candidate therapy, supplied by Ionis Pharmaceuticals, is made of a strand of 20 nucleotides and has five nucleotides on either end that are chemically modified with 2'-O-methoxyethyl groups to make it bind tau mRNA more tightly. The central 10 nucleotides remain unmodified, to take advantage of a naturally occurring enzyme called RNase H, which recognizes the bound complex and destroys the tau mRNA.

To test the potential therapeutic, Miller used mice engineered to express high levels of human tau protein and thus typically suffer from neuron death and brain shrinkage. The researchers installed pumps on the animals’ backs to slowly infuse the antisense oligonucleotide into their spines. The researchers found that it significantly lowered tau mRNA and tau protein, and they were pleasantly surprised to discover that the agent—which contains a high density of negative charge—dispersed throughout the brain. The oligonucleotide also prevented brain volume loss, neuron death, and even reversed preexisting tau clustering in the mice (Sci. Transl. Med. 2017, DOI: 10.1126/scitranslmed.aah7029).

“The ability of these antisense oligonucleotides to reverse pathology is exciting,” says Matthew D. Disney of Scripps Research Institute Florida. “Although these drugs are experimental and not without risks, they appear ready to be assessed for efficacy in humans.”

Miller’s team also administered two doses of the antisense agent via a spinal tap to cynomolgus monkeys and found that the oligonucleotide reduced tau protein in the spinal cord nearly as effectively as it did in multiple regions of the brain.

This approach “has a clear path toward a human clinical trial,” where the drug could be injected into spinal fluid, Miller contends. He notes that just one month ago, the Food & Drug Administration approved the antisense oligonucleotide therapy Spinraza for a genetic disease called spinal muscular atrophy, in which motor neuron death causes muscle wasting. Spinraza was also developed by Ionis.