increased with disease stage. They also demonstrated
that CSF huntingtin levels decreased following suppression of huntingtin in the brain.
A Clinical Trial Nears Completion
Ionis Pharmaceuticals developed an antisense oligonucleotide that targets both the mutant and normal
alleles of huntingtin. Investigators subsequently began
a first-in-human phase I/IIa trial of the drug in patients with early Huntington’s disease. Participants
were randomized 3: 1 to drug or placebo at sites in the
United Kingdom, Germany, and Canada. The drug is
administered intrathecally, and maximal protein suppression occurs approximately four weeks later. Each
study participant will undergo intrathecal injections
every month for four months.
The trial’s primary objective is to evaluate the treatment’s safety and tolerability. Its secondary objective is
to examine the drug’s CSF pharmacokinetics. Finally, an
exploratory objective is to assess the treatment’s effect on
pharmacodynamic biomarkers and on clinical end points
of Huntington’s disease.
All of the participants have been enrolled in the
study, and Dr. Leavitt administered an intrathecal
infusion to the first subject at the Vancouver site in
September 2015. Participants are generally in good
health and have high levels of function. Thus far, the
researchers have found no evidence of significant adverse events or safety concerns, and the drug appears
tolerable, said Dr. Leavitt. Results of the trial should
be available in the coming months, he added. “This is
certainly exciting, and it is the first time we have been
able to bring a genetic therapy into the clinic for this
Other Therapies in Development
Wave Life Sciences also has created an antisense oligo-
nucleotide for Huntington’s disease that is in the late
preclinical stages of development. The company uses
a type of chemistry that allows it to control the stereo-
isomer composition of the nucleic acids. The therapy
targets specific single-nucleotide polymorphisms on
mutant huntingtin and therefore may not be appropri-
ate for every patient with Huntington’s disease. “This
[treatment] has at least the potential for allele-specific
targeting … and will hopefully be entering the clinic
fairly soon,” said Dr. Leavitt.
Other gene-therapy approaches require a vector, most
often a nonpathogenic adeno-associated virus (AAV), to
bring the treatment into the CNS. Several such therapeutic
candidates in preclinical development are close to entering
early human trials, said Dr. Leavitt.
UniQure is developing a form of AAV5 that ex-
presses an artificial micro-RNA that targets huntingtin.
The drug will require stereotaxic injection directly into
the brain. In one study, direct intraparenchymal injec-
tion of the drug significantly reduced levels of mutant
huntingtin in the putamen, caudate, and thalamus of
a minipig model of Huntington’s disease. The drug
had less effect in the cortex. Depending on where the
virus is injected, viral approaches generally have good
local targeting, but not necessarily widespread target-
ing, said Dr. Leavitt. Spark Therapeutics and Voyager
Therapeutics are also developing therapies similar to
that of UniQure. NR
Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis.
Neuron. 2012; 74( 6): 1031–1044.
Southwell AL, Smith SE, Davis TR, et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington
disease stage and decrease following brain huntingtin suppression. Sci Rep.
Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin
protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest.