Gene Silencing Shows Promise for Treating 2 Fatal Neurological Disorders
In 1996, it was discovered that mutations in the ataxin 2 gene cause spinocerebellar ataxia type 2 (SCA2), a fatal inherited disorder that primarily damages a part of the brain called the cerebellum, causing patients to have problems with balance, coordination, walking and eye movements.
Mutations in ataxin 2 that are associated with SCA2 cause the gene to have polyglutamine expansions, strings of repeated copies of the three letter genetic code, CAG, which stands for the amino acid glutamine. On average, symptoms appear earlier and are more severe for patients who have longer strings. People who have only 27-33 repeats will not develop SCA2 but have an increased risk for ALS.
Now, in two studies of mice, reported in Nature (12 April 2017), it was shown that a drug, engineered to combat the gene that causes SCA2, might also be used to treat amyotrophic lateral sclerosis (ALS), a paralyzing and often fatal disorder. For the study, it was found that the problems associated with SCA2, could be reduced by injecting mouse brains with a drug programmed to silence the ataxin 2 gene. In the second study, it was showed that injections of the same type of drug into the brains of mice prevented early death and neurological problems associated with ALS. The type of drug used is called an antisense oligonucleotide. Like an incomplete row of teeth on a zipper, these drugs are short sequences of DNA designed to bind to a portion of a gene’s instructions carried by a molecule called messenger RNA. This stops cells from manufacturing proteins, a process known as gene silencing.
An antisense oligonucleotide drug has been approved by the FDA for treating spinal muscular atrophy, a hereditary disorder that causes arm and leg muscle weakness and deterioration in children. Early phase clinical trials are being conducted on the safety and effectiveness of gene silencing drugs to treat several neurological disorders, including Huntington’s disease and an inherited form of ALS.
The authors worked with a pharmaceutical company to develop antisense oligonucleotides that silence the ataxin 2 gene rather than the CAG repeats. They then tested oligonucleotides on two lines of mice genetically engineered to have problems associated with SCA2 by programming neurons in the cerebellum to make mutant ataxin 2. In both lines, the oligonucleotides appeared to be effective. Mice injected with the drug were able to walk on a rotating rod longer than mice that received a placebo. Electrical recordings showed the drug restored the firing patterns of neurons in the cerebellum to normal. In addition to reducing ataxin 2 gene levels, the researchers found that the drug also restored the levels of several genes that appear to be decreased by mutant ataxin 2.
Meanwhile, authors used different mice to test the idea of combating ALS by silencing ataxin 2. These mice were genetically modified to manufacture high levels of the human version of TDP-43, a protein that normally regulates genes. The researchers investigated these mice because neurons from ALS patients often contain toxic clusters of TDP-43. The mice rapidly develop problems with walking and die early. Previous studies on yeast and flies by Dr. Gitler’s team and his collaborators have suggested that mutant ataxin 2 may control the toxicity of TDP-43. Compared to placebo, injections of the antisense oligonucleotides into the nervous system of the newborn mice extended their median lifespan by 35 percent and improved their ability to walk, while lowering ataxin 2 gene levels in the brain and spinal cord.
The authors saw similar results when they eliminated ataxin 2 by crossbreeding the TDP-43 mice with mice that are genetically programmed to have no ataxin 2 gene. The offspring lived longer and walked better than the TDP-43 mice. The brains of the offspring also had fewer toxic TDP-43 clusters than the TDP-43 mice.