Mutation stub

"Antisense" therapy restored the psyche of mice with Huntington's disease

Daria Spasskaya, N+1

Antisense nucleotide therapy has led to improved cognitive functions in mice with Huntington's disease, according to an article by Canadian scientists published in the journal Science Translational Medicine (Southwell et al., Huntingtin suppression restores cognitive function in a mouse model of Huntington's disease). In addition to mice, the drug was tested on monkeys.

Neuron (yellow) with accumulation of mutant huntingtin (red dot). National Institute of Neurological Disorders and Stroke.

Huntington's disease is a hereditary neurodegenerative disease that is associated with the accumulation of mutant huntingtin protein in neurons, and their subsequent death. The disease usually manifests itself in adulthood and is accompanied by progressive disorders of both motor and cognitive functions. It becomes difficult for patients to move, their coordination is disrupted, memory problems begin, progressive dementia and mental disorders. Currently, there is no treatment for this disease, only therapy that relieves symptoms.

The cause of neurodegeneration is a mutation in the huntingtin gene, namely, excessive accumulation of trinucleotide repeats in DNA – codons for the amino acid glutamine. A protein with a large amount of glutamine residues for some reason becomes toxic to cells. A similar phenomenon underlies some other neurodegenerative diseases – for example, the accumulation of glutamine in the protein ataxin-2 leads to the development of spinocerebellar ataxia. As with ataxia, suppressing the expression of the huntingtin gene should help eliminate the cause of the disease and possibly reverse its symptoms.

A promising way to prevent the synthesis of mutant protein in cells is to introduce antisense oligonucleotides into it against the mRNA of the target gene. These molecules are chemically modified chains of several nucleotides that "pair" with the desired mRNA according to the principle of complementary interaction, which ultimately leads to its destruction. Antisense oligonucleotides are injected into the cerebrospinal fluid, from where they penetrate into neurons. A similar drug has already been approved in the United States for the treatment of spinal muscular atrophy, a disease affecting the neurons of the spinal cord. A similar approach has also been tried for the treatment of Huntington's disease, and it has been shown that "antisense" therapy improves motor functions in sick mice.

A group of researchers from the Canadian University of British Columbia in collaboration with the American company Ionis Pharmaceuticals, which develops drugs based on antisense oligonucleotides, focused on the restoration of cognitive functions and therapy of mental disorders in Huntington's disease.

Since one copy of the mutant gene is sufficient for the development of the disease, most patients carry both mutant and normal copies. Although the functions of huntingtin are unknown, it is assumed that it is involved in a variety of processes, including the formation of long-term memory. Scientists have suggested that suppressing the synthesis of mRNA of only the mutant copy will allow a healthy protein to function normally in neurons, and this will lead to the preservation of mental and cognitive functions.

Previously, scientists created an entire panel of oligonucleotides against a number of polymorphisms in the gene that usually accompany an excessive number of glutamine codons. Four different molecules were tested on model mice with human huntingtin. Scientists have found that selective suppression of mutant protein synthesis even before the onset of symptoms leads to the fact that mice behave normally, and cognitive impairments do not develop in them (compared with the control group). In addition, suppression of both mutant and normal protein in later life facilitated mental disorders such as anxiety and depressive behavior.

To prevent cognitive impairment in humans, the drug must get into the neurons of the cortex and limbic system of the brain. The researchers tested on macaques with a relatively large brain compared to mice, that when injected into the cerebrospinal fluid, oligonucleotides eventually get to the right departments. Thus, this method of administration is quite suitable for the treatment of cognitive impairment in Huntington's disease in humans.

The introduction of modified oligonucleotides is not the only way to suppress unwanted gene expression. In August of this year, the first drug based on short interfering RNAs was approved in the United States for patients with a type of hereditary polyneuropathy caused by the accumulation of the protein transtiretin. Short RNA molecules in the composition of the drug should suppress the expression of transthyretin and prevent its synthesis. 

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