January 29, 2016
Researchers
at Oregon State University have announced that they have essentially stopped
the progression of amyotrophic lateral sclerosis (ALS),
or Lou Gehrig's disease, for nearly two years
in one type of mouse model used to study the disease - allowing the mice to
approach their normal lifespan.
The
findings, scientists indicate, are some of the most compelling ever produced in
the search for a therapy for ALS, a debilitating and fatal disease, and were
just published in Neurobiology of Disease.
"We
are shocked at how well this treatment can stop the progression of ALS,"
said Joseph Beckman, lead author on this study, a distinguished professor of
biochemistry and biophysics in the College of Science at Oregon State
University, and principal investigator and holder of the Burgess and Elizabeth
Jamieson Chair in OSU's Linus Pauling Institute.
In
decades of work, no treatment has been discovered for ALS that can do anything
but prolong human survival less than a month. The mouse model used in this
study is one that scientists believe may more closely resemble the human
reaction to this treatment, which consists of a compound called copper-ATSM.
It's
not yet known if humans will have the same response, but researchers are moving
as quickly as possible toward human clinical trials, testing first for safety
and then efficacy of the new approach.
ALS
was identified as a progressive and fatal neurodegenerative disease in the late
1800s, and gained international recognition in 1939 when it was diagnosed in
American baseball legend Lou Gehrig. It's known to be caused by the death and
deterioration of motor neurons in the spinal cord, which in turn has been
linked to mutations in copper, zinc superoxide dismutase.
Copper-ATSM
is a known compound that helps deliver copper specifically to cells with
damaged mitochondria, and reaches the spinal cord where it's needed to treat
ALS. This compound has low toxicity, easily penetrates the blood-brain barrier,
is already used in human medicine at much lower doses for some purposes, and is
well tolerated in laboratory animals at far higher levels. Any copper not
needed after use of copper-ATSM is quickly flushed out of the body.
Experts
caution, however, that this approach is not as simple as taking a nutritional
supplement of copper, which can be toxic at even moderate doses. Such
supplements would be of no value to people with ALS, they said.
The
new findings were reported by scientists from OSU; the University of Melbourne
in Australia; University of Texas Southwestern; University of Central Florida;
and the Pasteur Institute of Montevideo in Uruguay. The study is available as
open access in Neurobiology of Disease.
Using
the new treatment, researchers were able to stop the progression of ALS in one
type of transgenic mouse model, which ordinarily would die within two weeks
without treatment. Some of these mice have survived for more than 650 days, 500
days longer than any previous research has been able to achieve.
In
some experiments, the treatment was begun, and then withheld. In this
circumstance the mice began to show ALS symptoms within two months after
treatment was stopped, and would die within another month. But if treatment was
resumed, the mice gained weight, progression of the disease once again was
stopped, and the mice lived another 6-12 months.
In
2012, Beckman was recognized as the leading medical researcher in Oregon, with
the Discovery Award from the Medical Research Foundation of Oregon. He is also
director of OSU's Environmental Health Sciences Center, funded by the National
Institutes of Health to support research on the role of the environment in
causing disease.
"We
have a solid understanding of why the treatment works in the mice, and we
predict it should work in both familial and possibly sporadic human
patients," Beckman said. "But we won't know until we try."
Familial
ALS patients are those with more of a family history of the disease, while
sporadic patients reflect the larger general population.
"We
want people to understand that we are moving to human trials as quickly as we
can," Beckman said. "In humans who develop ALS, the average time from
onset to death is only three to four years."
The
advances are based on substantial scientific progress in understanding the
disease processes of ALS and basic research in biochemistry. The transgenic
mice used in these studies have been engineered to carry the human gene for
"copper chaperone for superoxide dismutase," or CCS gene. CCS inserts
copper into superoxide dismustase, or SOD, and transgenic mice carrying these
human genes die rapidly without treatment.
After
years of research, scientists have developed an approach to treating ALS that's
based on bringing copper into specific cells in the spinal cord and
mitochondria weakened by copper deficiency. Copper is a metal that helps to
stabilize SOD, an antioxidant protein whose proper
function is essential to life. But when it lacks its metal co-factors, SOD can
"unfold" and become toxic, leading to the death of motor neurons.
There's
some evidence that this approach, which works in part by improving
mitochondrial function, may also have value in Parkinson's disease and other
conditions, researchers said. Research is progressing on those topics as well.
The treatment is unlikely to
allow significant recovery from neuronal loss already caused by ALS, the
scientists said, but could slow further disease progression when started after
diagnosis. It could also potentially treat carriers of SOD mutant genes that
cause ALS.
http://www.medicalnewstoday.com/releases/305814.php
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