Can damage of dementia and Alzheimer's be undone?

A recent study suggests a possible treatment for Alzheimer's disease and other neurodegenerative disorders. Based on research on both mice and monkeys, some brain injuries caused by the toxic accumulation of tau protein, were prevented and even reversed.

Published in Science Translational Medicine, results of the work suggest that use of a tau antisense oligonucleotides (ASOs) might be an effective treatment for a variety of brain neurologic disorders. ASOs are single strands of either DNA or RNA that complement a chosen gene sequence. In the case of antisense RNA, ASOs prevent protein translation of certain messenger RNA (mRNA) strands by binding to them which prevents the strand from functioning.

The use of antisense oligonucleotides for gene knockouts in vertebrates, is now a standard technique in developmental biology used to study gene function. The techique was developed in 2000 by Janet Heasman PhD, Assistant Professor of Developmental Biology at Cincinnati Children's Hospital Medical Center in Ohio, and then working with frogs (Xenopus).

Currently researchers are conducting early phase clinical trials on the safety and effectiveness of ASOs designed to treat several neurological disorders, including Huntington's disease and Amyotrophic Lateral Sclerosis - ALS.

The U.S. Food and Drug Administration recently approved the use of an ASO for the treatment of spinal muscular atrophy, a hereditary disorder weakening muscles in infants and children.

Cells throughout the body normally manufacture tau proteins. They stabilize the microtubules that maintain the structure of a cell, and make up the internal structure of cilia and flagella. Microtubules are the platforms for transporting organelles and intracellular macromolecular assemblies, and are essential for chromosome separation during mitosis and meiosis.

In the brain, toxic forms of tau clump together inside dying brain cells forming non-functioning tangles. Alzheimer's disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy — are a few of the disorders resulting from tau tangles. Currently there are no effective treatments for combating them.

ASOs can be short sequences of either DNA or RNA, programmed to turn genes on and off. Sarah L. DeVos, a graduate student in Dr. Timothy Miller's laboratory in the Department of Neurology, Hope Center for Neurological Disorders, at Washington University in St. Louis, Missouri, tested the effectiveness of ASO gene sequences in mice. She introduced genetically engineering compounds to produce abnormally high levels of a mutant form of tau, then administered it to mice. Tau clusters began to appear in the brains of her 6-month-old mice and continued to accumulate with age. The mice developed neurologic problems and died earlier than control mice left alone.

She then injected ASO gene sequences into the fluid filled spaces of mice brains and found they reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid of those mice. The biologically engineered  compounds appeared to even reverse tau clustering in older mice previously administered the mutant form of tau. Upon post mortem examination, older mice had lived longer with healthier brains than mice receiving placebo injections.

"This compound may literally help untangle the brain damage caused by tau."

Timothy Miller MD, PhD, David Clayson Professor of Neurology, Washington University, St. Louis, Missouri, USA, and study senior author.

Experiments on non-human primates suggest that ASOs tested in mice could just as well reach important areas of larger primate brains to turn off tau. When compared with a placebo, two spinal tap injections of the ASO compound appeared to reduce tau protein levels in the brains and spinal cords of Cynomologus monkeys. Researchers also saw, as with the mice, that injections of the compound caused almost no side effects.

Nevertheless, the ASO must be fully tested for safety before it being tried on humans. Researchers are taking the next steps towards translating it into a treatment for a variety of human tau disorders.

Abstract
Accumulation of the protein tau directly correlates with cognitive decline in Alzheimer’s disease and other primary tauopathies. One therapeutic option may be to reduce total tau. In a new study, DeVos et al. identified antisense oligonucleotides (ASOs) that decreased human tau in the brains of transgenic mice with tauopathy and observed the reversal of preexisting tau pathology and tau seeding activity. Further, neuronal loss was halted and mouse survival extended. In monkeys, tau ASOs reduced tau in the brain and cerebrospinal fluid. Together, these data support investigating lowering tau in human patients who have tau-positive inclusions even after pathological tau has begun to be deposited.
Abstract

Accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer’s disease and other primary tauopathies. One therapeutic strategy may be to reduce total tau expression. We identified antisense oligonucleotides (ASOs) that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and preexisting phosphorylated tau and Thioflavin S pathology were reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In addition, mouse survival was extended, and pathological tau seeding was reversed. In nonhuman primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid. These data support investigation of a tau-lowering therapy in human patients who have tau-positive inclusions even after pathological tau deposition has begun.

Article: DeVos et al. Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy. Science Translational Medicine, January 25, 2017 DOI: 10.1126/scitranslmed.aah7029

This study was supported by grants from NINDS (NS078398, NS074194, NS057105) and National Institute on Aging (AG05681, AG044719), the Tau Consortium and Cure PSP. Ionis Pharmaceuticals supplied the authors with all of the antisense oligonucleotides in the described work.

For more information: http://www.ninds.nih.gov

About NINDS: NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institute on Aging: The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. It provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center at http://www.nia.nih.gov/alzheimers.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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A designer gene compound to prevent and reverse brain damage caused by tangled tau proteins,
is effective in mice and Cynomolgus monkeys. Hope exists that its effects may translate to humans.
Image Credit: Visembryo.com