Paolo Rossi Castelli 2 December 2021 5 min read

ALS, a new technique to block the wrong DNA

A therapy that can prevent DNA from copying genetic traits that may lead to hereditary forms of amyotrophic lateral sclerosis has been successfully tested (so far only in the lab).

One in ten cases of familial frontotemporal dementia (FTD - a type of juvenile dementia), and one in five cases of familial amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), share the same chromosome 9 genetic defect: the wrong repetition of base sequences (GGGGCC) - the building blocks of DNA - between 60 and several thousand times.

Depending on the type of cell affected by an erroneous sequence and the number of repetitions, the manifestations of the disease can be very different, but the cause is basically the same. So if the damage affects motor neurons (the nerve cells responsible for movement) it results in the gradual paralysis typical of ALS, while if the damage involves cells in the temporal area of brain lobes it causes dementia, which generally occurs at around 58 years of age. There are currently no effective treatments for either of these cases.

In a few years' time, however, the situation may change, as a study carried out by researchers from three prestigious US centres (the Scripps Institute, the Mayo Clinic and Johns Hopkins University) and published in Science Translational Medicine, shows that an erroneous DNA sequence can be corrected and restored almost to normal. The secret is to intervene on RNA (the molecule that acts as a 'mould' for the DNA and puts its instructions into practice) at the exact moment when the wrong sequence is copied into the RNA itself and then translated into proteins that are out of control. If transcription can be blocked at that moment it prevents degeneration. 

Early lab results are positive
American scientists synthesised a compound (a specific molecule) able to attach itself to the erroneous RNA sequence. This stops it from being transcribed and attracts enzymes that are already present in the organism and have a very useful function (probably to defend against foreign micro-organisms): the ability to destroy the erroneous RNA sequences.

In laboratory animals, this compound was able to reduce the concentration of dangerous proteins (those which trigger ALS or frontotemporal dementia) by 70%. Experiments in the lab with nerve cells from patients in cultures have produced a similar result. The molecule developed by US researchers also seems to have a long-lasting effect: just one injection in laboratory animals produced benefits that remained stable for six weeks.

Of course, there is still a great deal of testing to be done before this molecule’s effect can be directly verified on humans, but it seems like a promising start. Also, if a cure is discovered, the same RNA-based technique could be applied to other diseases caused by genetic abnormalities.

Not only for hereditary diseases
As mentioned above, the technique tested by American researchers has shown positive effects on hereditary forms of ALS and frontotemporal dementia. These, however, are only a small part of all the types of amyotrophic lateral sclerosis and FTD.

On the other hand it is also true that about 10% of non-hereditary forms of ALS are linked to abnormalities of chromosome 9 in some way. It is therefore important that there is a light at the end of the tunnel of extreme difficulties that have always accompanied the study and treatment of this disease.


Paolo Rossi Castelli

Journalist since 1983, Paolo has been dealing with scientific divulgation for years, especially in the fields of medicine and biology. He is the creator of Sportello Cancro, the site created by on oncology in collaboration with the Umberto Veronesi Foundation. He collaborated with the pages of the Science of Corriere della Sera for several years. He is the founder and director of PRC-Comunicare la scienza.