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An RNA-targeting drug alleviates ALS and dementia

Researchers at the University of Florida Scripps Biomedical Research centre have developed a drug capable of penetrating the blood-brain barrier and alleviating amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTP) in vivo. The work, published this week in Proceedings of the National Academy of Sciences, describes how the drug targets and subsequently degrades disease-causing RNA, which is produced through repeat expansion of a section of chromosome 9.

A broken record

Repeat expansions are sections of DNA that have duplicated over time. Continued expansion of these areas can leads to thousands of repeated sequences, which in some cases can cause a build-up of toxic mRNA and protein expression.

Familial ALS and FTP are caused by a GGGGCC repeat tract in the first intron of chromosome 9, often containing thousands of expansions. Whilst these diseases are generally considered separate entities, their common cause leads to some overlapping symptoms – namely cognitive decline and a loss of motor function. The RNA produced through transcription of this region contributes to disease pathology through the production of aberrant proteins and toxic foci, as described in Figure 1.

Figure 1: Image showing the different toxic entities which can be produced through repeat expansion in chromosome 9. Translation of toxic proteins is shown on the left, and protein-sequestering RNA foci are shown on the right. Adapted from Bush et al.

There are no cures for either ALS or FTP, and current therapies do not treat the cause of the illnesses. Matthew Disney and his Florida team therefore investigated a mechanism through which the lethal RNAs could be destroyed, preventing the production of any unwanted molecules.

A library of potential

To find a molecule that could degrade the expanded RNAs and prevent the production of toxic products, the team scanned through a library containing thousands of small compounds which have been previously identified as potential drug targets. When identifying a suitable candidate, it was vital that any mechanism to inhibit the aberrant RNAs would not impact the translation of the canonical protein. Additionally, the molecule needed to be able to cross the blood-brain barrier, which could be determined through analysis of the drug’s size and structure.

Sixteen compounds met these criteria and were taken forward for further consideration. Following analysis of these molecules to determine their potency, the team chose one compound to focus on. Derivatives were created to optimise its drug-like features and a final compound, dubbed “1” by the researchers, was selected as the lead molecule.

The drug acts by binding to the GGGGCC expansion and initiating natural RNA decay and splicing processes as part of a “quality control” mechanism. The researchers tested the drug in stem cell-derived neurons from patients and in transgenic mice models, in both cases finding that disease associated pathology had decreased. Furthermore, in the in vivo study, the mice appeared healthier following ongoing treatment with the drug.


ALS and FTP are not the only illnesses caused by repeat expansions within the genome. Huntington disease and myotonic dystrophy are two well-known examples, among many others. The work provides a proof-of-concept for the development of drugs that could tackle the root cause of these conditions and prevent the build-up of toxic, disease-inducing products.

Disney stated that the results described in this study can act as a “general approach for other neurological diseases”. Certain disease-causing repeat tracts can also harbour the same or similar repeated sequences and structures, and the researchers hypothesise that perhaps one single molecule could eventually be developed to target a multitude of diseases. The team will continue to analyse the drug, but for now the future looks bright.

More on these topics

ALS / Dementia / Drug Development / Repeat Expansion / RNA