#AAN2018 – New Molecular Therapies May Be Treatment Strategy for ALS, Study Suggests

New antisense oligonucleotide (ASO) molecular therapies targeting the most common gene mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia reduced brain disease hallmarks in a mouse study, researchers found.

The study, “Stereopure Antisense Oligonucleotides Preferentially Knockdown G4C2 Repeat-Containing C9ORF72 Transcripts: A Potential Therapeutic Approach for the Treatment of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) (N2.002),” will be presented as part of the session “Neuroscience in the Clinic: Antisense Oligonucleotide (ASO) Therapy” at the 2018 American Academy of Neurology (ANN) Annual Meeting, April 21-27 in Los Angeles.

The presentation will be delivered by Robert H. Brown Jr., an MD and PhD and a professor of neurology at the University of Massachusetts Medical School, and will take place at 4:45 p.m. on April 23 Pacific Time. The study’s abstract was recently published in the journal Neurology.

An alteration in the C9orf72 gene is the most frequent cause of ALS and FTD. Specifically, a large repeat expansion of sequences consisting of four guanine and two cytosine (G4C2) nucleotides — the building blocks of DNA and RNA — reduces the amount of  C9orf72 and leads to the production of abnormal RNA molecules (transcripts from DNA) and toxic aggregates made of dipeptide repeat proteins (DPRs).

In a collaboration between Wave Life Sciences and UMass Medical School, scientists aimed to target RNA molecules that contain the G4C2 expansion using tiny stereopure ASO molecules, which bind to RNA.

With this approach, investigators intended to prevent the accumulation of the abnormal molecules while avoiding changes in C9orf72 protein levels.

Scientists used a molecular assay of RNA and patient-derived induced pluripotent stem cells (iPSCs) — which can differentiate into virtually any cell and tissue type in the body — to generate neurons, and discovered ASO genetic sequences that decreased the amount of the abnormal RNA.

They then confirmed the activity of these ASO sequences in patient-derived fibroblasts and in mouse neurons under a microscope. Scientists also used transgenic mice containing the human  C9orf72 gene with a repeat expansion to assess the ASO’s efficacy.

Researchers optimized the ASO chemistry, which resulted in potent, stereopure ASOs, as confirmed in the activity assays. The molecules exhibited improved the in vitro stability compared to other ASOs.

In addition, injecting these ASOs into the brain of transgenic mice led to a stable reduction of repeat-containing C9orf72 transcripts, abnormal RNA, and toxic aggregates of DPRs, without changing C9orf72 protein levels.

“These results suggest that preferential targeting of repeat-containing transcripts using stereopure ASOs may be a viable therapeutic approach for the treatment of ALS and [frontotemporal dementia],” the researchers wrote.