An international effort to combat Huntington’s disease has led to the establishment of a new treatment approach that can convert the responsible protein from its diseased form back to its normal form to resume its function. This research program, supported by the EU and Korea’s National Research Foundation, involved major international collaboration among Professor Ji-Joon Song’s team from the Department of Biological Sciences; the Institute for BioCentury at KAIST;  ProQR Therapeutics, a Dutch biotechnology company; Université Grenoble Alpes inFrance; and KTH Royal Institute of Technology, Sweden..

Huntington’s disease is a hereditary condition caused by a mutation in the huntingtin protein. Parts of the brain are prevented from working normally, leading to a progressive neurodegenerative disorder. The symptoms usually appear around 30 to 50 years of age and include difficulty in concentration, memory lapses, depression, mood swings, and involuntary movement of the body and limbs. The conditions gradually worsen, and they generally become fatal over a period of about 20 years at which point the patients require full-time nursing care. The disease currently has no known cure, although medication and therapy can help alleviate the symptoms. 

The mutation that leads to this disease adds an expanded stretch of glutamine amino acids called polyglutamine to the huntingtin protein. A cleavage near this stretched polyglutamine is known to be the cause of the disease. Normally-functioning huntingtin is essential for the development of the brain and day-to-day activities. This complicates the treatment of Huntington’s disease because mutant huntingtin needs to be eliminated while preserving the normally-functioning huntingtin. 

Researchers showed that a mutation-resistant form of huntingtin can be obtained using antisense oligonucleotides (AON). This result has posed a major step toward finding a cure for Huntington’s disease. The findings came from empirical testing on mice, and it was seen that this disease-resistant form of huntingtin carried out normal functioning, was stable over a period of several months, and resistant to  pathogenic proteolysis, a process in which proteins break down. This discovery has raised hopes for a therapeutic treatment for Huntington’s disease.

The findings of this research were published in Journal of Clinical Investigation Insight under the title “A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function”.