Gene Silencing Observed to Treat Deadly Neurologic Disorders

Experimental drug may be able to treat spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis.

In 2 new animal studies, an investigational drug showed promise combating 2 deadly neurological disorders.

The drug was originally engineered to silence the gene that causes spinocerebellar ataxia type 2 (SCA2), but may also treat amyotrophic lateral sclerosis (ALS), according to the studies, both published by Nature.

The authors used an antisense oligonucleotide to treat mice models with SCA2 and ALS. These drugs are short sequences of DNA that bind to a specific portion of a gene’s instructions carried by RNA, which inhibits cells from creating proteins, according to the study. This process is called gene silencing.

“Our results provide hope that we may one day be able to treat these devastating disorders,” said senior study author of the first Stefan M. Pulst, MD.

The authors previously discovered that mutations in the ataxin 2 gene result in the development of SCA2, which is a rare, fatal disorder that damages the cerebellum. Patients with SCA2 experience problems with balance, coordination, walking, and eye movements.

SCA2-related mutations in ataxin 2 cause the gene to have polyglutamine extension, which are strings of repeated copies of the amino acid glutamine (CAG). Patients with longer CAG strings tend to develop symptoms earlier, while those with 27 to 33 strings will have an increased risk of ALS, according to the study.

In the first study, the authors worked with a pharmaceutical manufacturer to develop an antisense oligonucleotide that silences the ataxin 2 gene. The drug was then injected in 2 different mice models of SCA2.

The authors found that injecting a gene silencing drug in the brains of SCA2 mice models resulted in reduced symptoms of the disease. The mice were able to walk on a rotating rod longer compared with placebo mice. Additionally, administering the antisense oligonucleotide to mice was seen to have normalized the firing patterns of neurons in the cerebellum, according to the study.

The authors of the accompanying study previously discovered a link between ataxin 2 and ALS in yeast and fly studies. The second study also showed that the injected drug prevented early mortality and neurologic issues from ALS, according to the study.

“Surprisingly, the ataxin 2 gene may act as a master key to unlocking treatments for ALS and other neurological disorders,” said senior author of the accompanying study Aaron Gitler, PhD.

The authors of the second study analyzed the use of the drug in mice that were modified to create high levels of human TDP-43. While this protein regulates genes in normal patients, toxic clusters gather in the neurons of patients with ALS and cause disability.

“Our antisense oligonucleotides prevent cells from reading the blueprint for the ataxin 2 gene,” said lead author of the first study Daniel R. Scoles, MD.

Compared with placebo, newborn mice treated with antisense oligonucleotides were observed to have their lifespan increased by 35%, in addition to improved ability to walk, according to the study. Treated mice also had lower levels of ataxin 2 in the brain and spinal cord.

The authors observed similar findings in the offspring of ataxin 2 knockout mice and TDP-43 mice. The offspring lived longer, walked better, and had fewer toxic clusters of TDP-43 than TDP-43 mice, according to the study.

“Antisense oligonucleotides provide researchers with a promising tool for studying the underlying causes of many disorders and developing gene-targeting treatments,” said Amelie Gubitz, PhD, program director at National Institute of Neurological Disorders and Stroke (NINDS).

Thus far, the FDA has approved an antisense oligonucleotide for the treatment of spinal muscular atrophy. Researchers are also exploring the efficacy of gene silencing in treating Huntington’s disease, an inherited form of ALS, along with other neurological disorders.

Both Pulst and Gitler noted that additional research is needed before the experimental formulation of the drugs can be tested in human patients, and both teams are moving towards that goal, the study concluded.

“Many years of research on yeast and flies laid the ground work for these exciting results,” said Daniel Miller, PhD, program director NINDS. “They demonstrate that rigorous studies on simple disease models can lead to powerful insights that help us understand and potentially treat seemingly untreatable disorders."