Current treatments only alleviate the symptoms, as there is no way of halting 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.
“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,” says Edvard Smith, senior physician and professor at Karolinska Institutet’s Department of Laboratory Medicine. “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 comprise 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.
“We are fairly confident that this will also work since our oligonucleotides were taken up spontaneously by the cells,” says Professor Smith. “The idea is to administer them into the cerebrospinal fluid.”
Antisense therapy is itself not a novel or untested method. The first oligonucleotide-based drugs 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.
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More information: undefined undefined. OUP accepted manuscript, Nucleic Acids Research (2017). DOI: 10.1093/nar/gkx111
Journal reference: Nucleic Acids Research search and more info website
Provided by: Karolinska Institutet