News of Another Possible Tau Clearance Therapy

Tauopathies, a category that includes Alzheimer's disease, are neurodegenerative conditions characterized by the accumulation of altered forms of tau protein into solid neurofibrillary tangles. This is only one of a range of proteins that exhibit this sort of behavior with advancing age, such as the various forms of amyloid, and any comprehensive future toolkit for rejuvenation will have to incorporate the means to clear out this unwanted and damaging metabolic waste. In recent years, a few signs of progress towards tau clearance therapies have emerged, and while aimed largely at treating the later stages of Alzheimer's disease at the present time, a successful therapy of this class is something that probably should be applied to everyone on a periodic basis in later life. We all accumulate altered tau, and the only differences between someone with a tauopathy and someone without are matters of degree and time.

Under ordinary circumstances, the protein tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that damage brain cells. Such tangles are a hallmark of Alzheimer's and other neurodegenerative diseases. But researchers have shown that levels of the tau protein can be reduced - and some of the neurological damage caused by tau even reversed ­- by a synthetic molecule that targets the genetic instructions for building tau before the protein is made. The findings suggest that the molecule - known as an antisense oligonucleotide - potentially could treat neurodegenerative diseases characterized by abnormal tau, including Alzheimer's.

Researchers studied genetically modified mice that produce a mutant form of human tau that easily clumps together. These mice start showing tau tangles at around 6 months of age and exhibit some neuronal damage by 9 months. To reduce tau, the researchers used an antisense oligonucleotide, a kind of molecule that interferes with the instructions for building proteins. Genes in the DNA are copied into RNA, a messenger molecule that carries the instructions for building a protein. Antisense oligonucleotides bind to the messenger RNA and target it for destruction before the protein can be built. Such oligonucleotides can be designed to target the RNA for almost any protein.

The researchers administered a dose of the anti-tau oligonucleotide to 9-month-old mice every day for a month and then measured the amount of tau RNA, total tau protein and tangles of tau protein in their brains when the mice were 12 months old. The levels of all three were significantly reduced in the treated mice compared with mice that received a placebo. Importantly, levels of total tau and tau tangles in the brains of treated 12-month-old mice were lower than in untreated 9-month-old mice, suggesting that the treatment not only had stopped but reversed the buildup of tau.

By the time this strain of genetically modified mice reaches 9 months of age, the hippocampus - a part of the brain important for memory - typically is visibly shrunken and shows dying neurons. But with the oligonucleotide treatment, the shrinkage and cell death were halted. There was not, however, any evidence of reversal of neuronal death. The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behavior, cognitive performance and motor capabilities. All of these functions can be impaired in people with Alzheimer's disease and other tau-related neurodegenerative diseases.

The researchers were intrigued by the possibility of designing studies to lower tau in people, but first they needed to see how the oligonucleotide worked in an animal more similar to people than a mouse. The researchers treated groups of healthy cynomolgus monkeys with two doses of placebo or oligonucleotide, one week apart, directly into the cerebrospinal fluid that surrounds the spinal cord and brain, just as would be done with human patients. Two weeks later, they measured the amount of tau protein and RNA in the monkeys' brains and cerebrospinal fluid. The oligonucleotide reduced both tau RNA and protein in the brain, and this reduction was mirrored in the cerebrospinal fluid.



In a timely development for the above potential Tau therapy, Oligonucleotides finally seem to be overcoming their delivery problems:

"More worryingly for the development of RNAi therapeutics, Alnylam halted development of its GalNAc-conjugated therapeutic revusiran for hereditary amyloidosis this October after reporting more deaths among patients receiving the drug in a Phase 3 trial than among those on a placebo. Despite attempts to reassure investors that other drugs in its pipeline use a newer GalNAc technology, the company saw its market value nearly halve overnight."

Posted by: Jim at January 26th, 2017 11:17 AM
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