VANCOUVER—Antisense oligonu- cleotides hold promise as treatments
for Huntington’s disease, according to an
overview delivered at the 21st International Congress of Parkinson’s Disease and
Movement Disorders. Preclinical evidence
suggests that these treatments are safe and
will decrease levels of mutant huntingtin
in the brain. The first clinical trial of an
antisense oligonucleotide for Huntington’s
disease is currently under way and fully
enrolled. Results will be available in the
near future, said Blair R. Leavitt, MDCM, Professor of
Medical Genetics at the University of British Columbia
What Are Antisense Oligonucleotides?
Antisense oligonucleotides are small, artificial units of
DNA that are modified chemically to have a long halflife. They can be targeted to bind to any RNA in the
body, and when they bind with huntingtin messenger
RNA, they prevent production of mutant huntingtin
protein. In theory, this action should prevent all subsequent pathology and delay or prevent the onset of
Huntington’s disease, said Dr. Leavitt.
Among the advantages of antisense oligonucleotides
is that neurons and glia take them up freely. They reach
the desired areas of the brain without requiring a vector
to introduce them. Antisense oligonucleotides are stable, have a long term of activity, act in a dose-dependent
manner, and have reversible effects. “They are much like
our classic small-molecule drugs, so we are comfortable
bringing these therapies into clinical development,” said
Preclinical Data Indicate Safety
Kordasiewicz and colleagues infused 75 mg of an anti-
sense oligonucleotide directly into the brain of a mouse
model of Huntington’s disease (ie, BACHD
mice) over 14 days. They observed a de-
cline in huntingtin RNA that endured for as
long as three months. The treated mice had
better motor coordination and performed
better on the rotorod test. The treatment
also slowed the loss of brain mass and im-
proved hypoactivity and anxiety.
The investigators also showed that antisense oligonucleotide reached the brain after intrathecal administration to monkeys.
The treatment reduced huntingtin levels by
approximately 50% in the cortex, and by between 20%
and 25% in deep brain structures.
A Potential Biomarker of Target Engagement
To gauge treatment efficacy in humans, neurologists
need a noninvasive way to measure levels of huntingtin in the brain. It is not yet possible to measure brain
huntingtin levels directly using imaging, but CSF levels
of huntingtin could be a surrogate measure, Dr. Leavitt
Dr. Leavitt and colleagues developed an ultrasensitive single-molecule counting immunoassay that successfully quantified mutant huntingtin in the CSF of
patients with Huntington’s disease. Mutant huntingtin
was undetectable in healthy controls. Patients with manifest Huntington’s disease had three times more mutant
huntingtin than asymptomatic mutation carriers did.
Huntingtin levels increased as the disease progressed.
In addition, huntingtin concentration predicted cognitive and motor dysfunction.
The investigators observed similar findings after they
used microbead-based immunoprecipitation and flow
cytometry to develop a second highly sensitive assay for
detecting mutant huntingtin. They demonstrated that
CSF levels of mutant huntingtin reflect brain levels of
the protein in mouse models of Huntington’s disease,
and in patients with Huntington’s disease, the levels
First Clinical Trial of a Genetic Therapy for
Huntington’s Disease Nears Completion
Preclinical evidence suggests that these treatments will be safe, and results of the
first clinical study will be available soon.
Blair R. Leavitt, MDCM