Huntington’s disease is a disastrous inherited disorder that produces a combination of psychiatric, neurological, motor, and cognitive symptoms. It’s caused by the multiple repetition in the genome of a specific DNA sequence in the HTT gene, which codes for a protein called huntingtin. The protein and the messenger RNA (mRNA) formed by the mutated gene damage the nerve cells in the brain and cause them to degrade. Researchers working at Karolinska Institutet in Sweden and University of Southern Denmark have managed to produce short synthetic DNA analogues (oligonucleotides) that bind directly to the gene that is mutated in Huntington’s disease and prevent the production of a protein that damages the nerve cells. The finding paves the way for modern approaches to treating the currently untreatable neurodegenerative disease.
Current treatments only ease the symptoms, as there is no way of arresting the progression of the disease. However, researchers are looking into a process called antisense therapy, in which short synthetic DNA analogues (oligonucleotides) bind to and inactivate mRNA to prevent it forming harmful proteins. Edvard Smith, senior physician and professor at Karolinska Institutet’s Department of Laboratory Medicine stated, “We’ve taken this a step further and created oligonucleotides that bind directly to the damaged DNA sequence and block the production of both mRNA and protein. It was thought by many to be too difficult to target the double-stranded DNA, but we have demonstrated that it actually works.”
The short oligonucleotides compose a combination of DNA and LNA (locked nucleic acid) and binds to the repeated CTG sequence in the HTT gene. When the researchers delivered them into cell lines from patients with Huntington’s disease, they observed a substantial reduction in the production of mRNA and protein. The next step will be to test the method on mice. Professor Smith stated, “We are fairly confident that this will also work since our oligonucleotides were taken up spontaneously by the cells. The idea is to administer them into the cerebrospinal fluid.” Antisense therapy is itself not a novel or untested method. The first oligonucleotide-based medicines were approved back in 1998 for the treatment of cytomegalovirus infection, and as recently as December 2016 another was approved in the USA for spinal muscular atrophy.