REVIEW
Huntingtin-Lowering Strategies in Huntington’s Disease: Antisense
Oligonucleotides, Small RNAs, and Gene Editing
Neil Aronin, MD1* and Marian DiFiglia, PhD2
1
Department of Medicine and RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA
2
Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA
ABSTRACT: The idea to lower mutant hunting-
tin is especially appealing in Huntington’s disease (HD).
It is autosomal dominant, so that expression of the
mutant allele causes the disease. Advances in RNA and
gene regulation provide foundations for the huntingtin
gene (both normal and mutant alleles) and possibly the
mutant allele only. There is much preclinical animal
work to support the concept of gene and RNA silenc-
ing, but, to date, no clinical studies have been
attempted in HD. Preventing expression of mutant hun-
tingtin protein is at the cusp for a human trial. Antisense
oligonucleotides delivered to patients with amyotrophic
lateral sclerosis have been well tolerated; small RNAs
administered to rodent and nonhuman primate brain
knocked down huntingtin messenger RNA (mRNA);
short-hairpin complementary DNA of microRNAs can be
The Basic Principle in Huntington’s
Disease Is Its Genetic Underpinning
Huntington’s disease (HD) is foremost an autosomal-
dominant disease. The mutant gene is sufficient to con-
vey the disease to offspring of an affected parent to
produce the disease. The mutation is an increase in a
series of CAG repeats near the start site of the hunting-
tin gene.1 There are a few gaps in the genetic principle.
The extent of CAG expansion does not exactly predict
onset and progression of the clinical manifestations in
HD—cognitive impairment, depression, and abnormal
------------------------------------------------------------
*Correspondence to: Dr. Neil Aronin, Department of Medicine, University
of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA
01655; Neil.Aronin@umassmed.edu
Relevant conflicts of interest: Nothing to report.
Full financial disclosures and author roles may be found in the online ver-
sion of this article.
Received: 1 August 2014; Revised: 12 August 2014; Accepted: 15
August 2014
Published online 27 August 2014 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26020
expressed in adeno-associated virus to provide long-
term silencing of huntingtin mRNA and protein. We
expect that these approaches will be ready for clinical
studies in the near future, once safety has been vali-
dated. Our understanding of gene editing—changing
the huntingtin gene itself—is rapidly progressing. Har-
nessing our knowledge of transcription and translation
should push scientific creativity to new and exciting
advances that overcome the lethality of the mutant
gene in HD. VC 2014 International Parkinson and Move-
ment Disorder Society
K e y W o r d s : Huntington’s disease; huntingtin; gene
regulation; clinical trial
movements. The correlation has much splay, consistent
with the idea that other genes or environmental factors
influence HD progression.4 A small number of patients
have de novo expansion of CAG repeats in series, with-
out inheriting a mutant huntingtin gene,5 evidence for
spontaneous generation of a new HD kindred. It is
postulated that a high, but normal, CAG copy number
expands into the disease range. For the vast majority of
patients, the expanded CAG repeat explains the disease
presentation.
Animal studies serve as good avenues to test
huntingtin-lowering strategies, but incorporate impor-
tant caveats. The mode for the CAG repeat expansion
in patients is 42, with some variance among reports.6
This number is important to bear in mind. Few animal
studies, including those emphasizing therapeutics,
work with CAG repeat expansions at 42; most use
animals with over 70 CAG repeats, even over 100
repeats, a rare repeat number in patients. The mutant
huntingtin gene product has many properties of nor-
mal huntingtin. Patients with mutation in both copies
of the gene do not have a more severe course of the
Movement Disorders, Vol. 29, No. 11, 2014 1455

A R O N I N A N D D I F I G L I A
disease than those with a single copy; the mutant gene
with the highest number of repeats characterizes the
clinical course of the disease.7 For practical reasons of
scientific study, animal models of HD need to develop
signs of disease quickly (months), compared to
patients in which changes in the brain occur over dec-
ades before disease onset. At the time of diagnosis,
based on clinical symptoms and signs, we speculate
that many neurons have degenerated in the striatum
and cortex. Therefore, the mutant gene in HD pro-
duces a protein (or messenger RNA [mRNA]) with
small effects on normal physiology long before disease
onset. Animal models lack the timing of onset of HD,
transforming it from a chronic- to a rapid-onset
disease.
Targeting Huntingtin Transcripts
Offers Promising Preclinical Results
Two viable treatments reduce huntingtin mRNA
and thereby mutant huntingtin protein: antisense oli-
gonucleotide (ASO) and RNA interference (RNAi).
Each has a central, but not exclusive, enzymatic pro-
cess inherent in the actual mRNA silencing.2,3,8-11
ASOs are DNA-based small molecules. Alterations
in oligonucleotide bonds extend their half-life in cells,
improve duration of action, and lead to good pene-
trance into cells.11 As with small interfering RNAs
(siRNAs), ASOs do not cross the blood–brain barrier
(BBB). They can be injected into the lumbar space and
traverse into brain cells.12 It appears, in nonhuman
primates, that the neocortex and local spinal cord take
up ASO against huntingtin mRNA, but sufficient in
striatum to cause knockdown of huntingtin mRNA or
protein. Optimization of dose or delivery approach of
ASO may improve therapeutic response.12 In mouse,
ASOs achieve good knockdown and appear to be safe
(without detailed histology) for at least a few
months.12 ASOs use RNase H to cleave huntingtin
mRNA.11 Rnase H recognizes DNA/RNA complexes
and, presumably, act by this enzyme, although other
mechanisms are possible.11 Allele-specific knockdown
has been achieved with this molecular technology.13
An advantage of ASOs over RNAi is that introns can
be targeted, giving ASOs a wider range of site to tar-
get. ASOs can enter the nucleus and target introns and
exons in unspliced RNA. Thus, DNA technologies
offer a valuable resource for oligonucleotide treat-
ments in HD.
ASO treatment in patients with HD has not yet
been reported on. But, ASO has been used in another
autosomal neurodegenerative disease: superoxide dis-
mutase 1 (SOD1) familial amyotrophic lateral sclerosis
(ALS).1 Infusion of ASO (ISIS 333611) into the intra-
thecal space of patients with SOD1 ALS was well tol-
erated overall. Many patients experienced adverse
1456 Movement Disorders, Vol. 29, No. 11, 2014
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effects (AEs) of the lumbar puncture, but not of the
drug itself. Treatment of SOD1 or HD patients would
probably require multiple administrations. Patients tol-
erated retreatment. The pathology of SOD1 ALS cen-
ters in the spinal cord, adjacent to the delivery site of
the ASO. Whether lumbar infusion will reach the
striatum and cortex in patients with HD will need to
be tested. The route of infusion (directly into the stria-
tum or into the intracerebral ventricular system) might
be considered for therapy.
RNAi uses a series of events in which a small RNA
(siRNA) forms a complex with mRNA, bringing an
assembly of proteins to the targeted mRNA (RNA
silencing complex, or RISC). The protein, Argonaute
2, has primacy in this complex and serves as a nucle-
ase to cleave the mRNA target. Destroying the mRNA
target prevents translation of the protein, in our case,
huntingtin. RNAi requires a small starting RNA, usu-
ally approximately 21 nucleotides for each strand of a
duplex (siRNA). Once in a cell, the siRNA associates
with several proteins to form the RISC, so that a sin-
gle strand (guide strand) binds to the target mRNA
and protein in RISC cleave it. siRNAs have good, but
imperfect, fidelity; other mRNA targets might be
affected.14,15 siRNAs require a small sequence with
complementarity to detect the mRNA target (seed
sequence), but they can have single-nucleotide discrim-
ination. siRNAs that are manufactured to make spe-
cific sequences can be designed to detect single-
nucleotide differences in mRNA alleles and can be
applied to single-nucleotide polymorphism (SNP) het-
erozygosities. The molecular machinery that underpins
RNAi through siRNAs is in place in mammalian cells
and neurons.16 It is thought that the guide strand of
siRNA and endogenous small RNAs, microRNAs
(miRNA, or miR), use the same set of proteins in
RISC.
A novel iteration of RNAi is the use of single-
stranded RNA (ssRNA) for decreasing huntingtin pro-
tein.17 ssRNA are modified, stabilized small RNAs
that have good spread after intraparenchymal adminis-
tration in mouse brain. The ssRNAs are more potent
than unmodified siRNAs (most designed for therapy
will probably be modified to improve stability).
Because ssRNAs reduce huntingtin protein, but not
huntingtin mRNA, they might invoke RNA repression,
rather than elimination, as the mechanism of action.
The ssRNA knocked down mutant huntingtin in a
human fibroblast from patients with HD. The mouse
knockdown worked when the CAG repeats were
greater than 100 in series. However, rare patients
have CAG expansions of this size. It is conceivable
that the high number of CAG repeats might make pos-
sible the ssRNA-based knockdown of the mutant hun-
tingtin allele. A more relevant huntingtin allele-specific
silencing would be testing ssRNA in mutant hunting-
tin mRNA in a range of 40 to 50 CAG repeats,

H U N T I N G T I N - L O W E R I N G
because this is the range typical for Huntington’s dis-
ease. The ssRNA modification demonstrates that crea-
tive modifications of siRNA can offer improvements
in therapy by knocking down mutant huntingtin
protein.
miRNAs are naturally occurring small RNAs that
populate cells in mammals, especially neurons.18 Clas-
sically, whereas siRNAs are generally made with full
complementarity to the mRNA target, miRNAs fre-
quently have mismatches, except in the seed sequence.
miRNAs affect the 30 untranslated region (UTR)
mostly to reduce stability of mRNA and increase its
destruction.18 To place into context, the polyA tail of
mRNA has a greater effect on mRNA stability than
do miRNAs, but miRNAs work in a cumulative, coop-
erative manner, with synergistic effects on mRNA
stability.
siRNAs, ssRNAs, and miRNAs have therapeutic
value. siRNA can be introduced into the brain
directly, enter neurons and glia, and reduce huntingtin
mRNA and protein.19,20 The sequence of siRNA can
be formulated to distinguish between two polymorphic
alleles of huntingtin.21,22 Huntingtin alleles have
SNPs, some of which are frequent in the Western
European population.21 Five siRNAs can be used to
distinguish between mutant and normal alleles in up
to 80% of patients with HD.21 One of the SNP heter-
ozygosities accesses 50% of patients with HD. The
sites of the SNP heterozygosities are in the open read-
ing frame and the 30 UTR. The practical use of SNP
heterozygosities needs to be confirmed in vivo. A com-
pelling advantage of siRNA use is its limited duration
of effect. Estimated influence is 2 to 4 weeks. If unto-
ward effects are found, such as ASOs, siRNAs can be
stopped. Furthermore, siRNAs can be modified.
Naked siRNAs are short-lived, but phosphorothiate
modification extends survival. Possibly, other modifi-
cations can be tested to modify half-life and delivery
into cells. A caveat for siRNA base RNAi is that
safety of siRNA against innate immunity will need to
be tested.
A problem for siRNA-based therapy in HD is brain
access. Direct administration would require bilateral
injection into the striatum and regions of the cortex.
The state of the art for siRNA delivery lags behind the
siRNA design and efficacy. As reported, pumps can
inject siRNA into a single striatum, shown in nonhu-
man primates.20 The disease, however, affects both
caudate and putamen in the striatum and many areas
of the cortex, criteria that ought to be considered in
the engineering for siRNA delivery.
Recent advances in vesicular trafficking might pro-
vide another avenue for delivery of small molecules:
siRNA, ssRNA, miRNA, and ASO. Exosomes are
vesicles (50-120 nm) that originate in the lysosomal
system, leave cells with their contents, and are taken
up by nearby cells. In essence, exosomes might be
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S T R A T E G I E S I N H D
delivery packages facilitating intercellular communica-
tion, including trans-synaptic.23,24 Current investiga-
tions address critical questions. What are exosomal
contents? How many small molecules can be loaded?
Can exosomes deliver sufficient amounts to transmit
molecular therapy? A wave of excitement emanated
from the finding that exosomes expressing rabies virus
glycoprotein (RVG) can cross from the circulation to
the neurons in brain, deposit siRNAs, and knock
down a protein contributing to Alzheimer’s disease in
rodents.24 It should be noted that naked siRNAs
(short-lived) were used, and more-stable siRNA can be
studied. The pharmacodynamics of RVG exosomes in
large animals is not established. Finding cells to pro-
duce exosomes for patient therapy will take careful
selection. Exosomes constitute a delivery system in its
infancy, but offer promise for small-nucleotide–based
therapies.
Short-Term Delivery Turns Into
Long-Term Gain, With Caveats
miRNAs have critical strengths for treatment of
HD. First, they can be sculpted to fit multiple targets.
A seed sequence can be made to detect both hunting-
tin mRNA alleles. Second, miRNAs fit into a short
hairpin, a structure that has a loop at the apex, has
similar strands of RNA at its base, and incorporates
sites for cleavage in the nucleus (drosha enzyme) and
in the cytoplasm (dicer enzyme). The result is a tem-
porary two-stranded RNA. The guide sequence is gen-
erally selected to enter RISC. Targeted mRNA
knockdown can ensue by rapid mRNA cleavage and
removal, destabilization of mRNA and slow removal,
or translational repression in which the mRNA does
not proceed to protein production, but survives none-
theless. Third, the miRNA short hairpin can be
inserted into a virus. A commonly used virus type is
adeno-associated virus (AAV). Another is lentivirus.
AAV has multiple serotypes with different properties
of cellular uptake. It is thought (based on limited
information) that a particular AAV serotype varies
uptake based on mammalian species and cell type
(e.g., neuron and glia).25 AAV resides in the nucleus,
but does not integrate into genomic DNA, unlike len-
tivirus that integrates in the genome.
AAV is used for gene therapy and, experimentally,
delivery of miRNA. Two promoters have been tested:
Pol II and Pol III (U6). Both produce abundant miR-
NAs from short hairpin complementary DNA inserted
into the AAV as cargo. Short hairpin (double-stranded
DNA with a DNA loop connecting the two DNA
strands) is processed by DICER in the cytoplasm to
make siRNA, or drosha in the nucleus and DICER in
the cytoplasm to make miRNA. AAV2 with U6 can
be toxic in mice, presumably because of excessive
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A R O N I N A N D D I F I G L I A
siRNA production.25,26 The cell type most affected in
HD, called striatal medium spiny neurons, degenerate.
Exportin-5, which transports short hairpin RNA
(shRNA) and other RNAs from the nucleus to the cyto-
plasm, is sequestered by overproduction of siRNA.
Loss of exportin-5 function may be toxic.27 Safety of
AAV-delivered miRNA depends on the extent of
miRNA expression and selectivity in targeting.
AAV is generally delivered by direct brain injection,
because, in the current technology, few neurons will
take up AAV from the circulation.28,29 AAV adminis-
tration is best achieved in the brain by convection
enhanced delivery, under constant pressure.30 Entry
into at least 40% of neurons and variable numbers of
glia is likely. Immune-neutralization antibodies (Abs)
prevent cellular uptake of AAV. Presence of these Abs
would be expected to limit repeated injections of
AAV. In theory, immune-neutralization Abs observed
in the circulation31 might be found in the brain, but
actual data are lacking.
AAV continues to deliver its cargo for many years in
nonhuman primates and humans.32 The goal of the ther-
apy would be that single administration of AAV with a
short-hairpin–containing microRNA (shRNAmir) into
the striatum and areas of the cortex silences mutant
huntingtin for many years. The short hairpin is proc-
essed to produce the miRNA, which is approximately
20 nucleotides in length. Studies in large brain animals
(e.g., sheep, pigs, and nonhuman primates) should be
performed to test for safety, immune neutralization,
spread of AAV, and knockdown of human mutant hun-
tingtin. AAV-shRNAmir has been used to ameliorate
neurodegeneration of mutant huntingtin in mice,26,33,34
and short-term studies of safety in nonhuman primates
look promising.35,36 An improvement in AAV-based
therapy would be regulation of AAV-shRNAmir produc-
tion in vivo, so that miRNA production can be curtailed
or shut off. In vitro tet-off promoters use a bacterial
protein to respond to an antibiotic; how humans would
respond to this protein is uncertain. “Tet” regulation in
animals is not fully controllable.
In theory, AAV-based systems for delivery of hun-
tingtin gene shRNAmirs incorporate long-term benefits:
a single injection; expression in neurons in affected
brain areas; evidence in mammals for huntingtin silenc-
ing; and a plethora of AAV serotypes to be taken up in
many brain cells. Eventual use will depend on spread in
the brain and safety of shRNAmir.
Can the Expanded CAG in
Huntingtin mRNA Make It Vulnerable
to No-Go Decay?
Translation is highly regulated. Molecular machin-
ery is geared to maintain an efficient, predictable poly-
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ribosomal translation rate. Slowing ribosomes along
mRNA allows intercession by surveillance molecules
that can interrupt ribosomal progress and destroy the
mRNA. Reducing the amount of factors that aid
translation across lengthy CAG repeats (as in HD) can
decrease production of mutant huntingtin.37 We spec-
ulate that processes that delay translation through the
CAG repeats in HD might have allele-specific silencing
properties. For example, in animal models of HD in
which the CAG is extraordinarily increased to greater
than 200 CAG repeats in series, two studies show that
the very high CAG expansion leads to increased lon-
gevity of the mice38,39 and reduction of huntingtin
mRNA.39 Electrophysiological defects are corrected.40
The puzzling result can be explained by destruction of
mutant huntingtin mRNA by no-go decay. The trans-
lational slowing and surveillance system response
blocks further translation through the vastly expanded
CAG repeat and removes the mutant mRNA from
translational participation. What is especially interest-
ing is that small molecules might detect slowed trans-
lation and take up a position on the ribosome to
block further translation, thereby offering a kind of
allele selective silencing.
Attacking the Huntingtin Gene
There are currently three speculative approaches to
edit genes in vivo: zinc finger nucleases (ZFNs); tran-
scription activator-like effectors nuclease (TALENS);
and Clustered Regularly Interspaced Short Palindromic
Repeats (CRISPR-Cas9).41-43 Each has a different mode
of action in their ability to cut DNA to begin the edit-
ing process. ZFNs cut with two nucleases (requiring
zinc) to cut DNA at a certain length apart. The two
DNA parts can reassemble, insert another piece of
DNA, or add a piece of DNA. TALENS use designed
proteins that bring nucleases to the target gene, thereby
causing double-stranded breaks. Zinc finger and TAL-
ENS nucleases offer the possibility for in vivo correc-
tion of mutations or corruption of mutant genes to
destroy production of the mutant protein in inheritable
disease genes. ZFNs can reduce mutant human hunting-
tin mRNA in a mouse model of HD.44 Administration
of ZFN overlapping CAG repeats into R6/2 mice
knocked down the human huntingtin mRNA, reduced
aggregates, and dampened aberrant behaviors. The
CAG expansion in these mice is large (over 100); use
of ZFNs in mice with 40 to 45 CAG repeats in a
human huntingtin gene will need to be established. Dis-
crimination between two human huntingtin genes
would make use of ZFN especially compelling. None-
theless, this finding advances the idea that attacking the
gene is a useful strategy for therapy.
CRISPR-Cas 9 causes cleavage through Cas 9.45-47
CRISPR has the role to bind to genes; binding sites

H U N T I N G T I N - L O W E R I N G
can be designed in a similar way to RNAi. CRISPR
brings Cas 9 to specific sites on the DNA, usually
with a requisite spacer, and cuts open the targeted
gene. The exposed ends of the DNA can undergo
homologous recombination (with an inserted piece of
DNA) to correct the gene mutation or disrupt the
gene to inactivate it. CRISPR has an added benefit. It
can bring other molecules to the gene or multiple
genes, favoring the addition of epigenetic factors. We
speculate (no data yet) that CRISPR, as with oligonu-
cleotides to RNA, might target DNA in genes in a
sequence manner, thereby allowing allele selective
silencing at the gene level. Elimination of the mutant
gene allele would reduce overall huntingtin expression
by one half; in contrast, changing both normal and
mutant huntingtin genes in a single cell would reduce
huntingtin expression fully.
How Much Knockdown of
Huntingtin Is Safe?
Lowering huntingtin overall has important conse-
quences. The level of huntingtin to support neuronal
functions is not established. Total loss of huntingtin in
development is lethal and loss in later life is harmful
to neurons.48,49 In monocytes from HD patients, 50%
of total huntingtin knockdown (mutant plus normal)
by RNAi restores normal cytokine function in the
monocytes.50 Extension of this study in mammalian
brain is underway. How much total huntingtin is
needed for maintaining neurons is not established.
Is Silencing the Huntingtin Gene or
mRNA Practical?
We are imbued with a wealth of opportunity to
silence mutant huntingtin. Abundant in vitro or in
vivo evidence supports mutant huntingtin knockdown
by ASO, siRNA, ssRNA, and viral (AAV) shRNAmir.
Treatment of mice is a first step in an in vivo model,
but enthusiasm of these data should be tempered
because access to neurons in a large brain to achieve
therapeutic benefit is a realistic hurdle. We become
inured of the success of gene silencing in mouse mod-
els because of easy access to neurons. Still, HD is
monogenic, has ready diagnosis through genotyping,
and has an educated, motivated patient population to
study. Are we ready for a clinical trial?
It is a leap of faith to assume that results in the
mouse, sheep, pig, and even nonhuman primate apply
in all aspects to humans. We cannot assume that
immune responses to AAV or neuronal uptake of
AAV serotypes are the same among mammals. Brain
sizes vary, presenting challenges to delivery of silenc-
ing agents. Whether RNA or DNA based, oligonucleo-
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S T R A T E G I E S I N H D
tide therapy in humans will probably be given as an
infusion, with the expectation that the salubrious
effects will last many weeks to several months. Single
injections of oligonucleotides into the brain would be
minimally instructive, given that neither spread nor
efficacy would be adequately tested in either the cor-
tex or striatum. Intraventricular delivery is an option,
but not yet established in nonhuman primates, which
have less than 10% of human brain size. Intraparen-
chymal administration could improve targeted ther-
apy; however, advances in engineering would need to
ensure sufficient bilateral infusion to the cortex and
striatum to evaluate effective therapeutics.
ASO therapy has been applied to neurodegenerative
disease. Under the conditions of the clinical experi-
ment, infusion of ASO has AEs from the lumbar punc-
ture, but not the drug itself. This finding is a phase I,
short-term study, but the results are encouraging.
Soon, a phase I study to test ASO for huntingtin might
be initiated. Huntingtin is less abundant than SOD1;
we do not know the threshold of safety for excessive
knockdown of both alleles in HD. This issue is appro-
priate to consider for safety evaluation. How to moni-
tor the distribution of the oligonucleotide in the
human brain is not established; the ASO should reach
the striatum and cortex, a challenge for intrathecal
infusion. Intraventricular infusion might offer better
distribution into cortical and subcortical structures.
siRNA delivery would probably be direct into the
striatum. As with ASO, bilateral spread to the stria-
tum and cortex presents a therapeutic hurdle. Once
long-term safety is established (6 months) in large ani-
mals, a phase I trial seems practicable for safety and
feasibility. To determine efficacy, short-term measure-
ments of the three categories of changes should be
apparent: cognition, mood, and motor. siRNA infu-
sion might depend on advances in engineering, given
that siRNA modifications do not enter the brain from
the cerebral fluid space particularly well. ssRNA might
be a feasible option for spread from the ventricles.
The promise of long-standing therapy underlies
AAV delivery of miRNA against huntingtin mRNA.
The prospect is exciting. Nonetheless, its safety must
be clear. Unlike oligonucleotides, expression of
miRNA cargo from AAV cannot be stopped. The
viruses are designed to express miRNA for years or
decades. Might too much miRNA expression affect
both huntingtin mRNA alleles to reduce levels below
a safe threshold? Might excess miRNA production
influence endogenous miRNA handling or affect off-
targets? These queries are currently unanswered. We
need to ensure safety of AAV and miRNA in a large
brain, preferentially in an animal with the mutant
huntingtin mutation. Careful study necessitates a firm
understanding of AAV serotype and promoters (pol II
vs. pol III), extent of miRNA production, as well as
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A R O N I N A N D D I F I G L I A
neuronal and glial spread. Use of AAV has the prom-
ise to establish long-term treatment with a single
application, a laudatory goal.
In theory, a combination of strategies would have
usefulness over a single treatment approach. For
example, ASO treatment by intrathecal injection
reduces huntingtin mRNA in the cortex, whereas
AAV-shRNAmir into the striatum would provide
long-term knockdown of huntingtin mRNA in the
striatum. The caudate and putamen in the striatum
are compact, whereas the cortex is marked by many
folds, a challenge for direct injection of viral therapy.
Together, the therapies could have overlapping distri-
butions in the cortex and striatum.
We considered recent discoveries that might have
application to HD. Delivery of oligonucleotides in
exosomes, especially if they cross the BBB, would
facilitate treatments, taking treatment from a neuro-
surgical strategy to an outpatient injection. Gene edit-
ing would eliminate continual treatments with ASO or
siRNAs for neurons that are edited. Allele-specific
editing to target the mutant huntingtin gene would
avoid complete loss of huntingtin in neurons. There is
not enough evidence to predict safety of complete
huntingtin silencing.
This is a transitional time for mRNA or gene-
directed therapies. We remain in discovery mode to bet-
ter grasp the potential and limitation of the therapies.
It is our hope that clinical trials are readied soon.
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