H D I N S I G H T S
HD Insights, Vol. 11 4
Copyright © Huntington Study Group 2015. All rights reserved.
By: Lise Munsie, PhD
1
Arber C, Precious SV, Cambray S, et al. Activin A directs striatal
projection neuron differentiation of human pluripotent stem cells.
Development. 2015Apr 1;142(7):1375-86.
2
Biagioli M, Ferrari F, Mendenhall EM, et al. Htt CAG repeat
expansion confers pleiotropic gains of mutant huntingtin function in
chromatin regulation. Hum Mol Genet. 2015 May 1;24(9):2442-57.
3
Mattis VB, Tom C, Akimov S, et al. HD iPSC-derived neural
progenitors accumulate in culture and are susceptible to BDNF
withdrawal due to glutamate toxicity. Hum Mol Genet. 2015 Mar 3.
pii: ddv080. [Epub ahead of print]
In stem cell research...
Generating GABAergic medium-sized spiny
neurons (MSNs) from human pluripotent
stem cell (hPSC) sources is a rapidly evolving
technique that holds much promise for HD
modeling and treatment. Arber and
colleagues describe a new method of
differentiating hPSCs to MSNs using Activin
A (activin).
1
Activin is part of the
transforming growth factor beta signaling
pathway, involved in neurogenesis and
neuronal cell type fate. Arber's paper
describes the ability of activin to produce a
much higher proportion of MSNs than
current techniques, and the ability of these
neurons to survive in grafts in rodent models
of HD.
Dr. Ihn Sik Seong's group makes an elegant
cell model of HD using embryonic stem cells,
producing six isogenic lines from one lineage.
One line expresses two copies of wild-type
mouse huntingtin (Htt) (Q7), an Htt null line,
while four heterozygous lines express one Q7
allele and one CAG expanded allele of 20, 50,
91, or 111 CAG repeats.
2
This paper explores
histone modifications in the presence of mHtt
and Htt, based on research indicating that Htt
acts as a polycomb recessive complex-2
facilitator. The authors show subtle
alterations to the chromatin landscape and
histone methylation states depending on
whether Htt or mHtt is present, and whether
cells are in a pluripotent
or differentiated state.
Mattis and his group
used HD-patient-derived
induced pluripotent stem
cells produced from non-
integrating technology to assess how HD and
juvenile-onset HD CAG repeat lengths affect
neuronal differentiation.
3
The group found a
significantly higher proportion of nestin-
positive cells in cultures derived from JHD
patients after 42 days of differentiation. Cells
with juvenile-onset HD CAG repeat length
suffer an increase in cell death with brain-
derived neurotrophic factor withdrawal, due
to glutamate toxicity. The authors posit that
this increase may be mediated through the
TrkB receptor.
1
Panegyres PK, Shu CC, Chen HY, Paulsen JS. Factors influencing the
clinical expression of intermediate CAG repeat length mutations of
the Huntington's disease gene. J Neurol, 2015. 262(2): p. 277-84.
2
Hobbs NZ, Farmer RE, Rees EM, et al. Short-interval observational
data to inform clinical trial design in Huntington's disease. J Neurol
Neurosurg Psychiatry. 2015 Feb 10. pii: jnnp-2014-309768. doi:
10.1136/jnnp-2014-309768. [Epub ahead of print]
3
Gabery S, Georgiou-Karistianis N, Lundh SH, et al.
Volumetric analysis of the hypothalamus in
Huntington Disease using 3T MRI: the IMAGE-HD
Study. PLoS One, 2015. 10(2): p. e0117593.
1
Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant
huntingtin protein in cerebrospinal fluid from Huntington's disease
patients. J Clin Invest. 2015 Apr 6. pii: 80743. doi: 10.1172/JCI80743.
[Epub ahead of print]
2
Monteys AM, Wilson MJ, Boudreau RL, et al. Artificial miRNAs
targeting mutant huntingtin show preferential silencing in vitro and
in vivo. Mol Ther Nucleic Acids. 2015 Apr 7;4:e234. doi: 10.1038/
mtna.2015.7.
3
Jimenez-Sanchez M, Lam W, Hannus M, et al. siRNA screen
identifies QPCT as a druggable target for Huntington's disease. Nat
Chem Biol. 2015 May;11(5):347-54.
H D I N S I G H T S
In the clinic...
A recent study assesses the clinical
manifestation of HD in patients who express
intermediate CAG repeat lengths.
1
A group
led by Panegyres examined subjects who had
repeats in the 27–35 range (at risk for
prodromal HD), 36–39 range (mixed
penetrance), or 40+ range (HD). No patients
with CAG repeat length below 35 developed
manifest HD. Smoking and being older than
65 correlated with manifest HD among those
with intermediate repeat lengths. Of note, a
high level of education was associated with
lower odds of manifest HD, and the authors
propose several hypotheses about
environmental, cognitive or epigenetic
factors.
A paper by Hobbs and colleagues in a group
led by Prof. Sarah Tabrizi assessed candidate
outcomes in HD patients in the imaging,
clinical and cognitive streams, at both short
(six-month) and longer (15-month) time
periods, in order to
further the guidelines
for assessing outcomes
in HD clinical trials.
2
This is the first study to
report significant effect
size in short time periods. The strongest
longitudinal changes were present in caudate
atrophy and ventricular expansion. Small
effect sizes were noted in other imaging and
clinical measures that will be useful over
longer time periods.
To date, there have been few studies assessing
changes in the hypothalamus, a brain
structure that may be responsible for the
sleep, emotional and metabolic changes
associated with HD. Hypothalamic changes
are noted up to 15 years before predicted
onset of manifest HD. In a recent PLoS One
article,
3
Gabery and colleagues explored
whether alterations to hypothalamic volume
may be linked to these symptoms. Using 3T-
MRI image data from IMAGE-HD, the group
compared hypothalamic volume between
patients before and after onset of manifest
HD. The group did not find any statistically
significant alterations in hypothalamic
volume, indicating that the hypothalamic
changes noted in previous studies are not
likely due to atrophy.
In the pipeline...
Wild and colleagues report in the Journal of
Clinical Investigation on an ultra-sensitive
method of quantifying mHTT levels in the
cerebrospinal fluid (CSF) of HD patients.
1
Using a single-molecule counting
immunoassay based on the MW1 antibody
specific for the expanded CAG tract, the
group demonstrated the ability to detect
mHTT in a disease- and onset-dependent
manner in the CSF of HD patients in two
cohorts. This assay will be useful as a
pharmacodynamic biomarker in clinical trials,
specifically in trials assessing HTT-lowering
strategies.
It has been shown that
allele-specific silencing
of mHTT can be
successful using small
interfering RNA
(siRNA) targeting the
expanded CAG tract, or single nucleotide
polymorphisms associated with the mHTT
allele. The Davidson group aimed to explore
whether specificity for the mHTT allele was
maintained when previously tested siRNA
sequences were moved into the group's
artificial mRNA expression system.
2
This
mRNA expression system may be more
amenable to sustained delivery of
knockdown than previously tested methods
of in vivo knockdown. The group tested their
system both in vitro and in vivo, and found
that only some of the previously tested
sequences were efficacious long term.
A report published in Nature Chemical Biology
by Jimenez-Sanchez and colleagues describes
a new therapeutic HD target extracted from
an siRNA screen focusing on genes that are
amenable to small molecule modulation.
3
The
most significant suppressor of mHTT toxicity
was glutaminyl-peptide cyclotransferase
(QPCT), an enzyme with glutaminyl cyclase
activity. The knockdown of this protein
inhibits mHTT aggregation, while
overexpression exacerbates aggregation.
Using pharmacophore models and other
known structures, the group designed QPCT
inhibitors. These inhibitors have positive
effects in several models of HD, and with
further development may become clinically
relevant.
Research Round-Up
