DNA therapy stopped neurodegeneration in mice

Daria Spasskaya, N+1

A joint team of researchers from the University of Utah, the University of Los Angeles, Stanford and Ionis Pharmaceuticals has published the results of preclinical trials of therapy for two severe neurodegenerative diseases - spinocerebellar ataxia of the second type and amyotrophic lateral sclerosis. The introduction of a short DNA molecule suppressing the synthesis of the protein ataxin-2 to sick mice led to an improvement in their condition and restoration of motor functions. The results of the work were published in two articles in the journal Nature (Scoles et al., Antisense oligonucleotide therapy for spinocerebellar ataxia type 2 and Becker et al., Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice).

Spinocerebellar ataxia and amyotrophic lateral sclerosis (ALS) – diseases with different origins but similar manifestations. In both cases, neuron degeneration and subsequent motor dysfunction are observed in patients, in the case of ALS it is more severe and leads to paralysis. There is no cure for these diseases yet.

Spinocerebellar ataxia of the second type has a hereditary nature and is caused by mutations in the ATXN2 gene (ataxin-2). One of its manifestations at the cellular level is a decrease in the excitability of Purkinje cells in the cerebellum, which are responsible for the accuracy of our movements. The mutant ataxin-2 gene accumulates repeats of the triplet encoding the amino acid glutamine, which leads to disruption of the functions of the corresponding protein. The authors of the work suggested that artificially reducing the expression of the ATXN2 gene in the cerebellum should alleviate the symptoms of the disease. 

The hypothesis was tested on a mouse model of ataxia, i.e. transgenic mice with a mutation in ataxin-2. So–called antisense oligonucleotides were injected into the cerebellum of sick mice - short chains of chemically modified DNA, complementary sequences of ataxin. Binding of these molecules to the matrix RNA of the gene should prevent the synthesis of the protein encoded in it. Having previously sorted through different variants of oligonucleotides, the scientists settled on one that most effectively suppressed the synthesis of ataxin, and it was already administered to animals. Antisense nucleotide molecules in the cerebellum got into Purkinje cells, where they contributed to a decrease in the amount of mutant ataxin. As a result, the nerve cells restored the ability to excite, and the motor skills of the animals improved. 

Purkinje cells containing therapeutic oligonucleotide (Scoles et al.)

A few years ago, a group of Stanford researchers led by Aaron Hitler discovered a link between ataxin-2 and amyotrophic lateral sclerosis. In people suffering from this disease, aggregation of the TDP-43 protein is almost always observed in neurons. Scientists have found that a decrease in the amount of ataxin correlates with a decrease in the amount of TDP-43 protein. Exactly how ataxin regulates the amount of TDP-43 is not entirely clear, but the authors of the study suggest that this is due to the ability of the former to induce the formation of stress granules, which include RNA and related proteins, including TDP-43. On a mouse model of ALS (in this case, the human version of TDP-43 was synthesized in large quantities in the body of animals), Hitler's group tested the effect of the introduction of the same oligonucleotide, which showed encouraging results in the case of ataxia. DNA therapy also worked this time - the life expectancy of the animals increased by a third, and motor functions partially recovered. 

Reducing the size of granules with TDP-43 when suppressing the synthesis of ataxin-2 (Becker at al.)

Antisense oligonucleotides have already been approved in the USA for the treatment of some neurodegenerative diseases, in particular spinal muscular atrophy. Probably, according to the results of preclinical tests on mice, DNA therapy of ataxia and ALS will enter the first phase of human trials. Considering that these diseases, although severe, are fortunately very rare, trials could cover a significant part of all patients.

Amyotrophic lateral sclerosis has been on the radar lately, including thanks to the Ice Bucket Challenge campaign. The foundation that launched this initiative raised a significant amount of money, which was effectively spent on the fight against ALS.

Portal "Eternal youth" http://vechnayamolodost.ru  17.04.2017