Question

Huntington's Disease: The role of the protein targeted by the antisense

Answer 1

Huntington's Disease is a heritable neurodegenerative disorder characterized by uncontrolled tremors (chorea), cognitive impairment, and psychiatric problems.

Antisense oligonucleotides are a type of gene silencing treatment for Huntington’s disease. Several of them are currently in development by pharmaceutical companies. Huntington’s disease is caused by mutations in the huntingtin (HTT) gene, which introduce long segments of repeating CAG nucleotides in the gene.

When a protein is being made, a gene is first “transcribed” or copied into a molecule called a messenger RNA. This messenger RNA then serves as a template for cells to make the corresponding protein.

The mutation seen in Huntington’s disease results in an abnormally large HTT protein being made, which is then degraded by the cell. This leads to the formation of toxic protein fragments, which damage the cells and cause neurodegeneration. Huntington’s disease is a dominant trait, meaning that a single copy of the mutated gene will cause the disease, even if the other gene copy is normal.

Antisense oligonucleotides are artificially created nucleotides, or pieces of DNA, which are complementary to the mutated sequence of the HTT messenger RNA. IONIS-HTT_Rx is an antisense oligonucleotide (ASO): an artificial chain of 12–25 nucleotides that is designed to prevent the production of protein from a specific gene.  IONIS-HTT_Rx was expected to diffuse into the brain, where it would suppress the production of the protein huntingtin in neurons. The antisense oligonucleotide binds to the HTT messenger RNA and prevents it from being translated into protein. In this way, the gene is “silenced,” or blocked, from creating toxic proteins.

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