YSM Issue 96.4

Gene Therapy
FOCUS
Why do treatments fail?
Sometimes there is an issue
with the treatment’s target.
Other times, the translation from an
animal model to humans presents too big
of a gap. Over the history of research on
gene therapy, such failures have brought
scientists closer to success.
The idea behind gene therapy is to treat
genetic diseases at their source by altering
a missing or faulty gene. For Parkinson’s
disease—in which loss of dopamineproducing
(dopaminergic) neurons leads
to slowness of movement and other severe
motor symptoms in late stages—this
approach has shown promise, but success
has, thus far, been out of reach.
Past research on gene therapy had
targeted a part of the basal ganglia—which
is responsible for motor control—called
the striatum. In mouse models, this was
quite successful, and several papers were
published on different genes targeting this
area. One of these papers, published in 1994,
was covered in the Yale Scientific Magazine
by Gautam Mirchandani (Vol. 66 No. 2), who
called it a promising study. The proposed
therapy was designed to target the gene for
tyrosine hydroxylase (TH), an enzyme that
is critical for synthesizing dopamine in a
Parkinson-like disorder. “Hopes are that
such a treatment will soon be available for
human benefit,” Mirchandani wrote. Yet,
these techniques have all since failed.
The problem, in many of these cases, was
actually the target. While easy to target in
a mouse, the basal ganglia in humans has
enlarged dramatically over the course of
evolution. Since the striatum forms such a
large part of the basal ganglia’s structure, it
was simply too large of a target. “It is very
difficult to cover it by injecting a virus,” said
Jim Surmeier, a professor of neuroscience at
Northwestern University Feinberg School of
Medicine. He is one of the many scientists
taking up the task of turning the coal of past
failures into the future diamonds that will
let gene therapy shine. “We fail more often
than we succeed,” Surmeier said. “What
distinguishes really good researchers is the
ability to learn from your failures.”
A New Target?
Surmeier’s research challenges prevailing
theories regarding the function of
dopaminergic neurons and their site of
action in Parkinson’s disease. Previous
researchers had assumed that loss of
dopamine in the striatum was sufficient
to cause the primary motor symptoms
associated with Parkinson’s. However,
Surmeier developed a new animal model
for Parkinson’s that involved
disrupting Complex 1, an
important protein for
energy generation, in
the mitochondria
of dopaminergic
neurons. The
difference in this
model was that,
unlike most
animal models
for Parkinson’s
which cause
rapid onset of
the severe motor
symptoms, this
model more closely
mimicked human
Parkinson’s with its slow
onset. Motor symptoms only became
apparent several months after gene editing.
This more realistic model led to both a new
potential cause of Parkinson’s in humans
and a better lens through which to study
how brain circuits contribute to the disease.
Using this model, Surmeier discovered
something unexpected. “When there was
clear loss of striatal dopamine release, the
animals were not Parkinsonian, contrary
to the prediction of the classical model,”
Surmeier said. His new theory takes into
account the structure of the basal ganglia.
While the striatum is a large complex within
this structure, there are other nuclei—
clusters of neurons that perform a specific
function—modulated by dopaminergic
neurons. One of these, which sits between
the basal ganglia and the rest of the brain,
is the substantia nigra pars reticulata (SNr).
While the traditional model of Parkinson’s
focuses on almost solely treating the
striatum, Surmeier proposed the SNr as
a new target for gene therapy. “The basal
ganglia are organized like a funnel, with the
SNr at the mouth of the funnel. Targeting
the mouth of the funnel is the best way to
control the output of the basal ganglia,”
Surmeier said.
Now armed with a location, Surmeier
needed a gene. In his study published in
Nature in 2021, he targeted aromatic acid
decarboxylase (AADC), a key enzyme that
converts the precursor levodopa into its final
form of dopamine. Levodopa is commonly
used as a treatment for Parkinson’s.
However, its effects wear off with time and
more advanced forms of the disease since
the dopaminergic neurons that
are dying are the primary
producers of AADC.
Thus, over time, the
brain begins to lack
sufficient AADC to
convert levodopa
into dopamine.
In this trial in
mice, Surmeier
was able to use
gene therapy to
give a new group
of neurons the
ability to express
A A D C — t h o s e
in the SNr—which
relieved motor deficits in
Parkinsonian mice.
Throughout the process, Surmeier
emphasized that one has to be willing to
both challenge past assumptions and learn
from past failures. When he first received
the data from his new Parkinsonian model,
Surmeier was skeptical enough to ask
others to repeat similar experiments, again
and again, when his results did not match
preconceived notions. “In science, we never
have truth in our hands,” Surmeir said. “It is
always an approximation.”
Yet Another Target?
Surmeier’s work is only the tip of the
iceberg when it comes to developing
gene therapies for previously intractable
diseases. His successful process of choosing
just the right nucleus for targeting, and just
the right enzyme to target for modification,
is the result of not just personal failures, but
also the failures, and successes, of many of
his colleagues.
One such colleague is Krzysztof
Bankiewicz at the Ohio State College of
Medicine. Bankiewicz has been interested in
dopamine and Parkinson’s disease since the
1980s, when he joined one of the first clinical
trials to restore normal dopamine levels in
the brain to reverse Parkinsonian symptoms.
The clinical trial intended to transplant
cells that could produce dopamine into the
www.yalescientific.org
December 2023 Yale Scientific Magazine 23