推 RIACC: 但是之前的測試 效果還是有限的 有其他基因療法在進行中 08/24 11:01
https://www.technologyreview.com/s/602193/manufacturing-dopamine-in-the-brain-with-gene-therapy/?utm_campaign=socialflow&utm_source=facebook&utm_medium=post
http://0rz.tw/Ilxob
Manufacturing Dopamine in the Brain with Gene Therapy
A novel solution for Parkinson’s patients who find their treatments wearing
off.
by Antonio Regalado August 22, 2016
Parkinson’s patients who take the drug levodopa, or L-Dopa, are inevitably
disappointed. At first, during a “honeymoon” period, their symptoms (which
include tremors and balance problems) are brought under control. But over
time the drug becomes less effective. They may also need ultrahigh doses, and
some start spending hours a day in a state of near-frozen paralysis.
A biotech company called Voyager Therapeutics now thinks it can extend the
effects of L-Dopa by using a surprising approach: gene therapy. The company,
based in Cambridge, Massachusetts, is testing the idea in Parkinson’s
patients who’ve agreed to undergo brain surgery and an injection of new DNA.
Illustration by Sergio Membrillas
Parkinson’s occurs when dopamine-making neurons in the brain start dying,
causing movement symptoms that afflicted boxing champ Muhammad Ali and actor
Michael J. Fox, whose charitable foundation has helped pay for the
development of Voyager’s experimental treatment.
The cause of Parkinson’s isn’t well understood, but the reason the drug
wears off is. It’s because the brain also starts losing an enzyme known as
aromatic L-amino acid decarboxylase, or AADC, that is needed to convert
L-Dopa into dopamine.
Voyager’s strategy, which it has begun trying on patients in a small study,
is to inject viruses carrying the gene for AADC into the brain, an approach
it thinks can “turn back the clock” so that L-Dopa starts working again in
advanced Parkinson’s patients as it did in their honeymoon periods.
Videos of patients before and after taking L-Dopa make it obvious why they’d
want the drug to work at a lower dose. In the ‘off’ state, people move in
slow motion. Touching one’s nose takes an effort. In an ‘on’ state, when
the drug is working, they’re shaky, but not nearly so severely disabled.
“They do well at first but then respond very erratically to L-Dopa,” says
Krystof Bankiewicz, the University of California scientist who came up with
the gene-therapy plan and is a cofounder of Voyager. “This trial is to
restore the enzyme and allow them to be awakened, or ‘on,’ for a longer
period of time.”
Voyager was formed in 2013 and later went public, raising about $86 million.
The company is part of a wave of biotechs that have been able to raise money
for gene therapy, a technology that is starting to pay off: after three
decades of research, a few products are reaching the market.
Unlike conventional drug studies, those involving gene therapy often come
with very high expectations that the treatment will work. That’s because it
corrects DNA errors for which the exact biological consequences are known.
Genzyme, a unit of the European drug manufacturer Sanofi, paid Voyager $65
million and promised hundreds of millions more in order to sell any
treatments it develops in Europe and Asia.
“We’re working with 60 years of dopamine pharmacology,” says Steven Paul,
Voyager’s CEO, and formerly an executive at the drug giant Eli Lilly. “If
we can get the gene to the right tissue at the right time, it would be
surprising if it didn’t work.”
But those are big ifs. In fact, the concept for the Parkinson’s gene therapy
dates to 1986, when Bankiewicz first determined that too little AADC was the
reason L-Dopa stops working. He thought gene therapy might be a way to fix
that, but it wasn’t until 20 years later that he was able to test the idea
in 10 patients, in a study run by UCSF.
In that trial, Bankiewicz says, the gene delivery wasn’t as successful as
anticipated. Not enough brain cells were updated with the new genetic
information, which is shuttled into them by viruses injected into the brain.
Patients seemed to improve, but not by much.
Even though the treatment didn’t work as planned, that early study
highlighted one edge Voyager’s approach has over others. It is possible to
tag AADC with a marker chemical, so doctors can actually see it working
inside patients’ brains. In fact, ongoing production of the dopamine-making
enzyme is still visible in the brains of the UCSF patients several years
later.
In some past studies of gene therapy, by contrast, doctors had to wait until
patients died to find out whether the treatment had been delivered correctly.
“This is a one-and-done treatment,” says Paul. “And anatomically, it tells
us if we got it in the right place.”
A new trial under way, this one being carried out by Voyager, is designed to
get much higher levels of DNA into patients’ brains in hopes of achieving
better results. To do that, Bankiewicz developed a system to inject the
gene-laden viral particles through pressurized tubes while a patient lies
inside an MRI scanner. That way, the surgeon can see the putamen, the brain
region where the DNA is meant to end up, and make sure it’s covered by the
treatment.
There are other gene therapies for Parkinson’s disease planned or in
testing. A trial developed at the National Institutes of Health seeks to add
a growth factor and regenerate cells. A European company, Oxford BioMedica,
is trying to replace dopamine.
Altogether, as of this year, there were 48 clinical trials under way of gene
or cell replacement in the brain and nervous system, according to the
Alliance for Regenerative Medicine, a trade group. The nervous system is the
fourth most common target for this style of experimental treatment, after
cancer, heart disease, and infections.
Voyager’s staff is enthusiastic about a study participant they call “
patient number 6,” whom they’ve been tracking for several months—ever
since he got the treatment. Before the gene therapy, he was on a high dose of
L-Dopa but still spent six hours a day in an “off” state. Now he’s off
only two hours a day and takes less of the drug.
That patient got the highest dose of DNA yet, covering the largest brain
area. That is part of what makes Voyager think higher doses should prove
effective. “I believe that previous failure of gene-therapy trials in
Parkinson’s was due to suboptimal delivery,” says Bankiewicz.
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蠻有趣的。
大意是說美國麻州生技公司最近測試一種基因療法，將製造AADC的DNA注入病人大腦中。
因為目前的L-Dopa帕金森藥物在服藥一陣子後後，因為AADC不足而無法將L-Dopa轉化成
多巴胺而使之喪失療效。目前測試的做法，雖然沒有提供預期的大幅改善，但已經對帕
金森病患有所助益。
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