Gene therapy in early stages of Huntington's disease may slow down
symptom progression

Date:
July 7, 2021
Source:
Johns Hopkins Medicine
Summary:
In a new study on mice, researchers report that using MRI scans
to measure blood volume in the brain can serve as a noninvasive
way to potentially track the progress of gene editing therapies
for early-stage Huntington's disease, a neurodegenerative disorder
that attacks brain cells.



FULL STORY ==========================================================================
In a new study on mice, Johns Hopkins Medicine researchers report that
using MRI scans to measure blood volume in the brain can serve as
a noninvasive way to potentially track the progress of gene editing
therapies for early-stage Huntington's disease, a neurodegenerative
disorder that attacks brain cells.

The researchers say that by identifying and treating the mutation known
to cause Huntington's disease with this type of gene therapy, before a
patient starts showing symptoms, it may slow progression of the disease.


==========================================================================
The findings of the study were published May 27 in the journal Brain.

"What's exciting about this study is the opportunity to identify a
reliable biomarker that can track the potential success of genetic
therapies before patients start manifesting symptoms," says Wenzhen Duan,
M.D., Ph.D., director of the translational neurobiology laboratory and professor of psychiatry and behavioral sciences at the Johns Hopkins
University School of Medicine. "Such a biomarker could facilitate the development of new treatments, and help us determine the best time to
begin them." Huntington's disease is a rare genetic disorder caused
by a single defective gene, dubbed "huntingtin," on human chromosome
4. The gene is passed on from parents to children -- if one parent has
the mutation, each child has a 50% chance of inheriting it. Huntington's disease has no cure and can lead to emotional disturbances, loss of intellectual abilities and uncontrolled movements. Thanks to genetic
testing, people can know if they have the disease long before symptoms
arise, which typically happens in their 40s or 50s.

For the study, Duan and her team collaborated with colleagues from Kennedy Krieger Institute in Baltimore, Maryland, who developed a novel method to
more precisely measure the blood volume in the brain by using advanced functional MRI scans. With the scans, they can map the trajectory of
blood flow in small blood vessels called arterioles in the brains of
mice engineered to carry the human huntingtin gene mutation that mirror
the early stages of Huntington's disease in humans.

Duan notes that there are many known metabolic changes in the brains
of people with Huntington's disease, and those changes initiate a brain
blood volume response in the disease's early stages. Blood volume is a key marker for oxygen supply to brain cells, which in turn supplies energy
for the neurons to function. But with Huntington's disease, the brain's arteriolar blood volume is dramatically diminished, which makes the
neurons deteriorate because of lack of oxygen as the disease progresses.



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In a series of experiments, the researchers suppressed the mutation in the huntingtin gene in mice, using a gene-editing technology known as CRISPR
-- a tool for editing genomes that allows the alteration of a DNA sequence
to modify gene function. Then, they used the MRI scanning technique and
other tests to track the brain function over time both of mice with the huntingtin mutation, in which they edited out the faulty gene sequence,
and a control group of mice in which the faulty gene was unedited.

The experiments assessed abnormalities in the trajectory of arteriolar
blood volumes in mouse brains with the Huntington's disease mutation
at 3, 6 and 9 months of age (pre-symptom stage, beginning of symptoms
and post-symptom stage, respectively). The researchers looked at whether suppression of the mutant huntingtin gene in the neurons could normalize altered arteriolar blood volumes in the pre-symptom stage, and whether
reduced expression of the huntingtin gene at the pre-symptom stage could
delay or even prevent development of symptoms.

"Overall, our data suggest that the cerebral arteriolar blood volume
measure may be a promising noninvasive biomarker for testing new
therapies in patients with Huntington's who are yet to show symptoms of
the disease," says Duan.

"Introducing treatment in this early stage may have long-lasting
benefits." When the researchers mapped the trajectory of cerebral
blood volume and conducted an assortment of brain and motor tests in the
mice at 3 months of age, and compared the test to those of the control
group, they observed no significant differences except in cerebral blood volumes. However, Huntington's symptoms in the mice with the huntingtin
gene started at 6 months of age and progressively worsened at 9 months, suggesting that altered cerebral blood volume occurs before motor symptoms
and atrophy of the brain cells -- typical traits of the disease.

The cerebral blood volume changes were also found to be similar to
those observed in patients with Huntington's disease before they start manifesting symptoms, which declines with the start of symptoms and
while the disease progresses over time.



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The researchers also analyzed the structure of the arteriole blood
vessels in the brains of mice with the mutant huntingtin gene at 3 and
at 9 months of age and found no differences in the numbers of vessel
segments in the pre-symptom stage. However, they observed that smaller
blood vessels had an increased density and reduced diameter, which may
be a vascular response to compensate for the impaired neuronal brain
function. This might suggest, the researchers conclude, that impaired
vascular structure leads to lowered arteriole blood volumes and possibly compromised ability to compensate for the loss in the symptom stage.

Considering that Huntington's disease symptoms depend not only on brain
cell loss but also on how neurons deteriorate, the researchers set out to determine if suppressing the huntingtin gene during the pre-symptom stage
in mice could delay or even prevent disease progression. To do that,
the researchers introduced the altered huntingtin gene to the neurons
in mice at 2 months of age and evaluated the outcomes at 3 months of age
(when no atrophy or motor deficits were present).

Remarkably, the researchers say, the cerebral arteriolar blood volume
in mice with the altered huntingtin gene was This suggests that the
altered cerebral blood volume during the pre-symptom stage in mice is
most likely due to neuronal changes in either activity or metabolism.

"Our findings demonstrate that significant changes in arteriolar cerebral
blood volumes occur before neurons start to degenerate and symptoms begin, further supporting the idea that altered cerebrovascular function is an
early stage symptom in Huntington's disease," says Duan. She explains
that these changes also indicate there's a pre-symptom therapeutic
window in which to test interventions. While no animal model replicates
all the symptoms of human Huntington's disease, this research offers an alternative system to study functional changes in the pre-symptom stage,
she says.

Further validation of these findings in human clinical trials would
facilitate development of efficient therapeutic interventions for patients
with Huntington's disease before they start developing symptoms. "The goal
is to delay or even conceivably prevent the manifestation of Huntington's disease altogether," says Duan.

========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hongshuai Liu, Chuangchuang Zhang, Jiadi Xu, Jing Jin, Liam Cheng,
Xinyuan Miao, Qian Wu, Zhiliang Wei, Peiying Liu, Hanzhang Lu, Peter
C M van Zijl, Christopher A Ross, Jun Hua, Wenzhen Duan. Huntingtin
silencing delays onset and slows progression of Huntington's
disease: a biomarker study. Brain, 2021; DOI: 10.1093/brain/awab190 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210707112510.htm

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