Karolinska Institute: Researchers working at Karolinska Institutet in Sweden and University of Southern Denmark have managed to produce short synthetic DNA analogues – oligonucleotides – that bind direct to the gene that is mutated in Huntington’s disease and prevent the production of a protein that damages the nerve cells. The discovery, published in the journal Nucleic Acids Research, opens the way for new approaches to treating the currently untreatable and deadly neurodegenerative disease.
Huntington’s disease is a devastating
inherited condition that produces a combination of neurological, motor,
cognitive and psychiatric symptoms. It is caused by the multiple
repetition in the genome of a specific DNA sequence (CAG/CTG) in the
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.
Current treatments only alleviate the symptoms, as there is no
way of halting the progressing 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 direct 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
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
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.
The present study was a collaboration between researchers
working at Karolinska Institutet, the University of Southern Denmark and
Karolinska University Hospital. Seven of the authors have submitted a
patent application related to their results. The study was financed with
grants from the Swedish Research Council, the CHDI Foundation (USA),
the Swedish Brain Fund, the Tore Nilson Foundation and the Swedish
CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression
', Zaghloul EM, Gissberg O, Moreno PMD, Siggens L, Hällbrink M, Jørgensen AS, Ekwall K, Zain R, Wengel J, Lundin KE, Smith CIE.
Nucleic Acids Research
, online 17 February 2017