Treatment shows promise in models of fatal neurological disorders

A drug designed to silence a gene called ataxin 2 improved neuron function in mouse models of neurological disease.Svisio/iStock/Thinkstock

Spinocerebellar ataxia type 2 (SCA2) is a condition characterized by progressive problems with movement. People with SCA2 initially experience problems with coordination and balance (ataxia). Over time, they may develop loss of sensation and weakness in the limbs, muscle wasting, uncontrolled muscle tensing, and involuntary jerking movements.

SCA2 is caused by mutations in the ATXN2 gene, which provides instructions for making a protein called ataxin-2. This protein is found throughout the body, but its function is unknown. Mutations that are associated with SCA2 cause the gene to have repeated copies of the three-letter genetic code for the amino acid glutamine. Normally, this segment is repeated in the gene about 22 times. People with 32 or more of these repeats develop SCA2. People with 27-33 repeats have an increased risk for another neurological disorder called amyotrophic lateral sclerosis (ALS), which is paralyzing and often fatal.

Two teams, led by Dr. Stefan Pulst at the University of Utah and Dr. Aaron Gitler at Stanford University, investigated whether a drug that turns off the ATXN2 gene could be used as a potential therapy in mouse models of these diseases. The studies were funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results from both studies were published on April 20, 2017 in Nature.

Pulst’s team worked with a pharmaceutical company to develop a set of antisense oligonucleotides. These drugs are like an incomplete row of teeth on a zipper. They are short sequences of DNA that bind a portion of the gene’s instructions and stop cells from manufacturing the protein—a process known as gene silencing. The team tested the oligonucleotides on two lines of mice with mutant ATXN2 genes. Mice injected with the drug were able to walk on a rotating rod longer than mice that received a placebo. In addition to reducing ATXN2 levels in the brain, the drug restored levels of several SCA2-related proteins.

Gitler’s group showed that injections of the same type of drug into the brains of mice prevented early death and neurological problems associated with ALS. The mice were genetically modified to manufacture high levels of the human version of TDP-43. Toxic clusters of TDP-43 are often found in neurons from patients with ALS. Compared to placebo, injections of the antisense oligonucleotides into the nervous systems of newborn mice lowered ATXN2 levels in the brain and spinal cord. It also extended their median lifespan by 35% and improved their ability to walk.

“Our results provide hope that we may one day be able to treat these devastating disorders,” Pulst says. More research is needed before these potential treatments could be tested in patients. Both labs are currently conducting further preclinical experiments.